ASCO Guidelines

Dr. Katherine Virgo discusses the latest evidence-based guideline recommendation updates regarding initial management of metastatic prostate cancer based on the new clinical trial results comparing triplet therapies (the addition of darolutamide, abiraterone, or enzalutamide to docetaxel plus androgen deprivation therapy) to standard of care. Dr. Virgo also discusses cost of treatment options and ongoing research questions in this field.

Read the full guideline, “‘Initial Management of Noncastrate Advanced, Recurrent, or Metastatic Prostate Cancer: ASCO Guideline Update” at www.asco.org/genitourinary-cancer-guidelines.

TRANSCRIPT

Dr. Scott Tagawa and Dr. Oscar Brouwer come on the ASCO Guidelines podcast to discuss the new EAU-ASCO Collaborative Guidelines on Penile Cancer. These comprehensive guidelines cover pathological assessment of tumour specimens, diagnosis and staging, local treatment of penile carcinoma, radical inguinal lymph node dissection, prophylactic pelvic lymph node dissection, surgical management, neoadjuvant and adjuvant chemotherapy, radiotherapy, systemic and palliative therapies for advanced penile cancer, follow-up, and quality of life. They highlight key recommendations, and describe the importance of a patient-focused and multidisciplinary approach to management of penile cancer.

Find more information about the guidelines at www.asco.org/genitourinary-cancer-guidelines

The full text of the guideline is available at https://uroweb.org/guidelines/penile-cancer

Conflict of interest disclosures:

Guideline Working Group 

Dr. Scott Tagawa 

Dr. Oscar Brouwer

TRANSCRIPT

Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. 

My name is Brittany Harvey, and today I'm interviewing Dr. Oscar Brouwer from the Netherlands Cancer Institute in Amsterdam, and Dr. Scott Tagawa from Weill Cornell Medical College in New York, co-chairs on the ‘ASCO-EAU Collaborative Guidelines on Penile Cancer’. 

Thank you for being here, Dr. Brouwer and Dr. Tagawa.

Dr. Scott Tagawa: Thanks very much.

Dr. Oscar Brouwer: Yeah, thanks for having us.

Brittany Harvey: Before we discuss this guideline, I'd just like to note that the guideline was led by the European Association of Urology, and the conflict of interest disclosures of the Guideline Working Group are publicly accessible through the European Association of Urology website linked in the show notes. Additionally, Dr. Brouwer's and Dr. Tagawa's individual disclosures are provided in the show notes of this episode. 

So, to jump into the content of this guideline, first, Dr. Tagawa, could you give us a general overview of the purpose and the scope of this collaborative EAU-ASCO Guideline?

Dr. Scott Tagawa: So, I think the key word there is collaborative. This was truly a collaborative effort, and I say that in a number of ways. So, the two key organizations, the EAU and ASCO, came together with a Memorandum of Understanding and got together from the very beginning in terms of developing the scope and then throughout the methodology for the guidelines. And then, on a practical basis, I'd say even more importantly, a collaboration between multiple physicians of different disciplines from across the world. Whether we're talking about surgeons, radiation oncologists, medical oncologists, pathologists, we had panel members from all over the world as well as patient representatives from all over the world. And patient representatives really played a key role in the development of this guideline. 

By way of background, penile cancer in most places is considered a rare disease. For example, in the United States, we expect around 2000 cases per year. In the genitourinary world, the next rare cancer is going to be testis cancer, which is going to be four or five times higher than that per year and nowhere near prostate cancer, for instance. So, just kind of put that into perspective. But, importantly, a disease that is a worldwide issue in a number of different ways. That includes the kind of general stigma of being diagnosed with that, the physical and emotional consequences of the diagnosis, as well as treatment. And then, because in part of its rarity, the lack of prospective randomized trials to really guide clinicians and that, I would say, that total package underscores the importance of coming together with a guideline.

Brittany Harvey: Great. Thank you for providing that background and perspective. 

So then, next, Dr. Brouwer, I'd like to review the key recommendations of this comprehensive guideline. Starting with what are the key recommendations regarding diagnosis and staging of penile cancer?

Dr. Oscar Brouwer: First of all, I guess just to underline what my colleague, Dr. Tagawa, just said, it's a worldwide guideline, international, multi-continental. I think that's quite a special thing. But it also poses a few challenges, of course, because cultural differences and treatments may differ, opinions as well, distances that patients have to travel, lots of factors there, and also economy, et cetera, et cetera. So, to find a consensus there has been one of the challenges. I think we did a good job there to really make it accessible to all patients and physicians, of course, in the world. 

When talking about diagnosis, I think comparing our new guidelines to old guidelines really emphasizes the new 2022 WHO classification in which distinction between HPV-positive and HPV-negative disease is highlighted. We increasingly have some knowledge on the difference between the HPV-related and the non-HPV-related penile cancers. I'd say it's about 50-50, the distinction. So, 50% is HPV-related, and 50% not HPV-related. But what we know from other cancers, for instance, that HPV-positive disease is associated with better prognosis than HPV-negative. This distinction is not so clear in penile cancer yet. And one of the reasons is just the lack of data, a lack of perspective for large studies, so to say. So, what we're really highlighting and underlining in the new guideline is the importance of doing HPV testing in all patients that have penile cancer, and that tissue is taken from. We chose to go for the cheapest and easiest but reliable methods to do so. So, immunohistochemistry of p16, to be exact. This is one of the important, I think, recommendations, or maybe even more than a recommendation; obligations we set to all physicians treating penile cancer. 

So, just in terms of diagnosis and in terms of staging, we all know that lymph node status is the most important factor determining survival. So, finding those lymph nodes, if they are involved with cancer, yes or no. So, if they are metastatic, yes or no, is of crucial importance. This has always been the case, but I think it cannot be emphasized enough. And in this new guideline, we again emphasize the importance of doing surgical lymph node staging in high-risk patients. And what's a little bit new is that we are more or less going to the direction of preferring central node biopsy as the best method to do so. You could also, of course, remove all the lymph nodes, what we call radical lymph node dissection. It's still possible inside our new recommendations, depending on availability of all the techniques or availability of expert centers in proximity. But I think we can all see that in terms of complication rates, central node biopsy is probably superior. So this is also one of the new things in terms of staging. 

Brittany Harvey: Absolutely. Thank you for those highlights of diagnosis and staging in the guideline. 

So, following those recommendations, Dr. Tagawa, and I know this is a large section, but what does the expert panel recommend for disease management of penile cancer?

Dr. Scott Tagawa: A single-sentence summary would say a multi-disciplinary approach in an expert center when possible. Re-emphasizing one of the statements that Dr. Brouwer made about sentinel lymph nodes; it appears to be better, but clearly is not available everywhere. And if I just make this US-centric for a minute, just within this country, where there are centers that are able to do it and have that expertise, there are centers that are not so far away that may not be able to do that. So regional differences within a single country that’s what happens. So, anyway, multi-disciplinary input, I think, is important for many diseases, including penile cancer.

A little bit of a segue, but one part of this guideline of which most of us are proud is that, front and center really, the introductory paragraph of the guidelines, where it really states that we need to really have this disease and the management patient-focused and that includes addressing some of the emotional aspects of the disease. Those are included in the management. But to kind of go through very quickly on a very high level, in the early stages management is mostly in the hands of the urologist. But sometimes there’s dermatologists and others, so when there is superficial disease, we talk about superficial therapy and I’m just going to leave it at that, many of them don’t have level 1 evidence, but there is, for instance, topical chemotherapy that can be helpful. 

And then, as the disease becomes more invasive, so does the treatment. So there’s sections on organ or penile sparing that is a reasonable option that needs to be done in a good multi-disciplinary system. That is a good and sometimes a preferred option when there is adequate staging for earlier stage disease. And then the more invasive the disease becomes is when the management needs to become more multi-disciplinary both in terms of workup as well as treatment. Where there is a consideration for, in certain situations, particularly in very locally advanced where it becomes unresectable at least in some eyes, where we say, “Okay, we’re actually going to recommend starting off with chemotherapy,” the intent is for surgery with an alternative of chemotherapy and radiation. And currently, there are no head-to-head trials, but those are both reasonable approaches for the most locally advanced disease setting. 

Taking a step back, if someone starts off with a little bit less locally advanced, so we’d say the alias, gross resectable, we would at least discuss in a multi-disciplinary setting what are the risk benefits of then post-operative therapy, whether that is radiation or chemotherapy, or both. I think all patients at least deserve the opportunity to have that discussion, and then that would be on an individual basis whether we decide to do that or not. Coming from the medical oncology-centric viewpoint where we really deal with systemic therapy, we don’t really have any randomized trials to say that one approach is preferred to another, so they’re kind of generic. But it does look like platinum chemotherapy, taxane chemotherapy are the most active current drugs. So when we’re looking at multi-agent therapy when the setting is a goal of cure, we’re generally saying platinum plus taxane combinations without being specific about doublets or triplets. Triplets when they can handle them, but not everyone can handle them. 

And then for metastatic disease whether it’s current or at presentation metastatic disease, the old guidelines actually said ‘don’t even bother’, but now that we have some effective drugs, we would say that for palliative purposes to come in with systemic chemotherapy, the same drugs that we talked about before. And then, there may be additional therapeutic agents. So we’re now in the genomic era where there has been at least an initial look at what are the genomics of HPV related, non-HPV related, and there may be some targets, we just are a little bit too early to say that there are absolutely some targets, but there definitely are recommendations for participating in clinical trials. There are some trials that are specific to penile cancer. There are other ones that are non-specific or basket trials. Let’s say any disease that has EGFR positivity, a patient with penile cancer may be able to get into that clinical trial or maybe meet a therapy-based trial, so considerations for the trials, I think, are important. 

Brittany Harvey: It sounds like multidisciplinary care is a key tenet of this guideline. You mentioned patient-focused care is also key in this guideline. So that leads nicely into my next question. But Dr. Brouwer, what are the key recommendations both for follow-up and quality of life? 

Dr. Oscar Brouwer Yeah so we have, like Dr. Tagawa already said, we have quite an elaborate section, not only in the introduction of the guideline but also a separate chapter at the end, really, to acknowledge the psychosocial, sexual impact this disease can have on patients. And again, I think it's more or less a plea for a form of centralized care for such a rare disease. We have a set of recommendations that we give in terms of follow-up and quality of life, and mainly several points that should really be discussed with patients, and support should be offered. So things like psychological sexual help, but also lymphedema therapist, physiotherapy in terms of complication management. And this mainly goes for patients that undergo lymph node surgery or treatment. And in our experience, if you don't see the disease often enough, you don't have all these things in place in your hospital to offer dedicated people that can do this. So I think that's something to consider in the future for healthcare in general when treating rare diseases such as these. But, yeah, like Dr. Tagawa said, our patient representatives have had a big role in this, and we're happy with that. So I recommend everyone to read it.

Brittany Harvey: Absolutely. You've both mentioned that this is a rare disease. So, in your view, Dr. Tagawa, what is the importance of this guideline, and how will it impact clinicians?

Dr. Scott Tagawa: There are certain centers that have high volume and certain countries that will have a high volume. For instance, areas in Brazil have a high volume. Whether there's a high volume or a low volume, like an average center in the United States, there haven't been any recent guidelines out there from any organization. So, the EAU has had an old guideline that was really out of date - updating that, number one. And number two, having the backing of two major organizations in the EAU and ASCO, I think is quite important to get this out there on a true international basis. Because not just in this disease, but in most diseases, when there is standardization of care, there's overall better outcomes, whether it's at the center that sees a lot or the centers that rarely see any. I think this document provides guidance, and, actually, take a step back for those that are interested, on the EAU website will be the entire very comprehensive guideline. So, someone that wants to get a lot of details, it's there, very comprehensive and honestly long, but it's, I think, an excellent reference document. And then, published in European Urology will be the summary guideline that has all the key points of the guidelines and summary in the text that will refer to the overall guideline for someone that wants to get through it on a quicker basis. That will also be published on the ASCO website just to kind of get that out there. A little bit of the side in terms of answering your question is that this is a rare tumor. We want everyone to have access to the best care possible, and if nothing else, it provides guidance in a setting where most clinicians don't have a lot of expertise.

Brittany Harvey: Definitely. And thank you for highlighting both the summary and full text of the comprehensive guideline. We'll provide those links in the show notes, too, for easy access for any listeners. 

And then, finally, you've both mentioned the impact this has for patients. But Dr. Brouwer, in your view, how will these guideline recommendations affect patients with penile cancer? 

Dr. Oscar Brouwer: Well, of course, it's our hope that it will be very beneficial for patients around the world. I think it cannot be emphasized enough that this initiative, in which ASCO, in this case United States group, has collaborated with the European one to make an international multi continental guideline, is quite rare, in urological cancers is the first one. I'm not even sure if there are many others like these. I do really believe it makes sense for rare diseases to not have several guidelines. It's confusing which guideline to choose, especially if there are contradictions. So I guess this initiative is the first step towards having more comprehensive, literal guidelines for such a rare disease. And I really do hope that it will help clinicians, especially when they don't have experience treating this disease, to really look at this guideline first. And in turn, of course, I hope that will benefit patients because they'll have, hopefully, access to better quality care that way. And especially, like we already touched upon, also the importance of early access to support and to palliative care throughout the whole disease process. I really hope that is something that will be offered to patients worldwide more frequently now because it is not only about treating the disease itself but also about the consequences, of course. And I really do think that people will benefit from that in terms of quality of life.

Brittany Harvey: Absolutely. I want to thank you both so much for your work on this comprehensive EAU-ASCO Guideline and for talking with me today and sharing your insights, Dr. Brouwer and Dr. Tagawa.

Dr. Scott Tagawa:  Thank you very much. It was a pleasure.

Dr. Oscar Brouwer: You're welcome. I would just like to add also a short opportunity, maybe just to thank all the panel members because it has been a huge effort. Not only an update, it has been actually rewritten from the ground up. So a lot of panel members, not only from the United States and Europe but also Canada, South America, patient representatives, all the associates that have helped. So it has been a big effort, and I congratulate and thank everyone. And thank you, Brittany, for the interview.

Brittany Harvey: Definitely, it was a large group and multidisciplinary effort. So thank you to them as well.

And also, thank you to all our listeners for tuning in to the ASCO Guidelines Podcast. To read the full guideline, go to www.asco.org/genitourinary-cancer-guidelines. I also encourage you to check out the companion episode on this guideline from EAU podcasts, which you can find on Apple Podcasts, Google Podcasts, and Spotify. You can also find additional ASCO guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe, so you never miss an episode.

 The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. Beverly Moy is back on the ASCO Guidelines Podcast to discuss the latest guideline rapid recommendation update regarding sacituzumab govitecan for patients with hormone receptor-positive HER2-negative metastatic breast cancer based on recent evidence published in TROPiCS-02. Dr. Moy reviews how this update intersects with the previous rapid recommendation update on trastuzumab deruxtecan and future areas of research that may impact further updates to this evidence-based guideline.

Read the latest update, "Chemotherapy and Targeted Therapy for Endocrine-Pretreated or Hormone Receptor–Negative Metastatic Breast Cancer: ASCO Guideline Rapid Recommendation Update" at www.asco.org/breast-cancer-guidelines.

TRANSCRIPT

Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one at asco.org/podcasts.

My name is Brittany Harvey and today I'm interviewing Dr. Beverly Moy from Massachusetts General Hospital in Boston, Massachusetts, lead author on ‘Chemotherapy and Targeted Therapy for Endocrine-Pretreated or Hormone Receptor–Negative Metastatic Breast Cancer: ASCO Guideline Rapid Recommendation Update’.

Thank you for being here, Dr. Moy.

Dr. Beverly Moy: Thank you for having me, Brittany. I'm glad to be here.

Brittany Harvey: Then first, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available in line with the publication of the guideline in the Journal of Clinical Oncology.

Dr. Moy, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Beverly Moy: I do not have any relevant disclosures.

Brittany Harvey: It's great to have you back on the podcast. Last we spoke, we were discussing the July 2022 rapid update of this guideline regarding the use of trastuzumab deruxtecan. What prompted the second rapid update to the guideline?

Dr. Beverly Moy: Thank you very much for that question, Brittany. The guidelines committee decided to issue another rapid guideline update because of the second interim analysis results of the TROPiCS-02 trial. This trial showed that sacituzumab govitecan had a significant improvement of over three months in overall survival compared to chemotherapy of physician’s choice in patients with pretreated metastatic hormone receptor positive and HER2/neu-negative breast cancer. So we felt that the strength of this data compelled the ASCO guideline ommittee to issue yet another update.

Brittany Harvey: Understood. So then, based off this strong data that you just mentioned from TROPiCS-02, what is the updated recommendation from the guideline expert panel?

Dr. Beverly Moy: So the guidelines expert panel really wanted to get this information out because we felt compelled that clinicians should be aware that sacituzumab govitecan is another treatment option for patients with endocrine-resistant metastatic hormone receptor- positive and HER2-negative breast cancer. So we felt that clinicians may use this drug in patients who have received at least two prior treatments in a metastatic setting.

Brittany Harvey: Okay, you just mentioned this is one of several treatment options. So as this new recommendation is implemented, what should clinicians know?

Dr. Beverly Moy: So, I think that clinicians really need to be aware that sacituzumab govitecan, which is a newer drug, as an antibody drug conjugate, it really does have a role in patients with metastatic hormone receptor positive, HER2/neu-negative endocrine-refractory breast cancer. I think clinicians have been used to this drug in the setting of metastatic triple-negative breast cancer, but the results of theTROPiCS-02 trial would show us that it actually has a lot of efficacy and even an overall survival benefit in patients with metastatic hormone receptor-positive breast cancer. So clinicians should be made aware that this is a treatment option that does give an overall survival benefit.

Brittany Harvey: Great. It's great to hear that there's an overall survival benefit with this drug.

So, in addition to that, how does this rapid update impact patients with hormone receptor-positive HER2-negative metastatic breast cancer?

Dr. Beverly Moy: So I think that it's important for clinicians to remember that patients with metastatic hormone receptor-positive HER2/neu-negative breast cancer, the first-line therapies are endocrine therapy and targeted therapies. But when their disease becomes endocrine refractory, we have several treatment options, and usually the standard is sequential single-agent chemotherapy. What this guideline update is telling us is that sacituzumab govitecan, when compared to other treatments of physician’s choice, really does improve overall survival and progression-free survival. So it really should be considered.

Brittany Harvey:  Excellent. And then finally, are there ongoing research developments that the panel is keeping an eye on for any future updates to this guideline? I know this guideline was last published in 2021 and there's already been two rapid updates to it.

Dr. Beverly Moy: Yes, that's a really great question, Brittany, because this is a very active field, and I think that it's important actually to take this guideline update with sacituzumab govitecan in the context of our last guideline update, which, as you said earlier, was with the other antibody drug conjugate trastuzumab deruxtecan. That was our last guideline update in patients who had what we call metastatic HER2 low disease, where trastuzumab deruxtecan had a significant overall survival advantage as well.

So what these two guideline updates are really pointing out is that there's this new class of drugs, these antibody drug conjugates, that have so much promise and so much activity in metastatic breast cancer, whether it's hormone receptor-positive or hormone receptor-negative. So future research really has to help us clarify how do we sequence these drugs most appropriately now that we have these two very active treatment options that have a significant overall survival advantage. And then research also has to really guide us into the resistance mechanisms that may be in common or not in common with these two antibody drug conjugates. So I think that we're really looking at results of future trials to see how best to sequence them, if they should be used earlier in treatment in the metastatic setting, and we await the results of those trials.

Brittany Harvey: Absolutely. We'll look forward to those future research developments and work with you and the panel to continuously update these guidelines.

So I want to thank you so much for your work leading these guideline rapid recommendation updates, and thank you for your time today, Dr. Moy.

Dr. Beverly Moy: Thank you, Brittany, for having me.

Brittany Harvey: And thank you to all our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

Dr. Praveen Vikas, Dr. Tyler Johnson, and Dr. Russell Broaddus present the ASCO endorsement of the Mismatch Repair and Microsatellite Instability Testing for Immune Checkpoint Inhibitor Therapy: Guideline From the College of American Pathologists in Collaboration With the Association for Molecular Pathology and Fight Colorectal Cancer. They discuss key evidence-based recommendations, focusing on the appropriate modality of testing (immunohistochemistry, polymerase chain reaction, or next generation sequencing) across multiple cancer types. Additionally, they cover the ASCO endorsement process, points of emphasis raised by the ASCO expert panel, and implications for clinicians and patients.

Read the full guideline endorsement, Mismatch Repair and Microsatellite Instability Testing for Immune Checkpoint Inhibitor Therapy: ASCO Endorsement of CAP Guideline at www.asco.org/molecular-testing-and-biomarkers-guidelines.

TRANSCRIPT

Brittany Harvey: Hello, and welcome, to the ASCO Guidelines podcast; one of ASCO's podcasts, delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at: asco.org/podcasts.

My name is Brittany Harvey, and today, I'm interviewing Dr. Praveen Vikas from the University of Iowa, Dr. Tyler Johnson from Stanford University, and Dr. Russell Broaddus from the University of North Carolina; authors on, 'Mismatch Repair and Microsatellite Instability Testing for Immune Checkpoint Inhibitor Therapy: ASCO Endorsement of CAP Guideline'.

Thank you for being here, Dr. Vikas, Dr. Johnson, and Dr. Broaddus.

Dr. Praveen Vikas: Sure.

Dr. Tyler Johnson: Thanks for having us.

Dr. Russell Broaddus: Thank you.

Brittany Harvey: First, I'd like to note that ASCO takes great care in the development of its guidelines, and ensuring that the ASCO Conflict of Interest policy is followed for each guideline product. The full conflict of interest information for this guideline endorsement panel is available online with the publication of the guideline endorsement in the Journal of Clinical Oncology.

To start, Dr. Vikas, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Praveen Vikas: I don't.

Brittany Harvey: And Dr. Johnson, do you have any relevant disclosures that are directly related to this guideline?

Dr. Tyler Johnson: I do not.

Brittany Harvey: And finally, Dr. Broaddus, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Russell Broaddus: I do not.

Brittany Harvey: Great. Thank you all for providing that information.

So, starting us off on the content of this endorsement, Dr. Vikas, what is the scope of this guideline endorsement?

Dr. Praveen Vikas: So, as you can see from the topic and headline, the guideline endorsement was focused on mismatch repair and microsatellite instability testing for immune checkpoint inhibitor therapy, and this is basically an endorsement by ASCO, of a guideline that was developed jointly by CAP, and others.

Brittany Harvey: Great. And then you just mentioned that this is an endorsement of the guideline developed by CAP and other organizations. Can you provide us an overview of how this guideline endorsement process works?

Dr. Praveen Vikas: ASCO definitely takes great pride in endorsing some of the guidelines that are relevant to our cancer community, and of course, mismatch repair and microsatellite instability testing has been one of those areas where there is a lack of clear guidance. So, when we were approached from CAP about endorsing this guideline, we definitely realized that there's not much published from most of our oncology community, so we were very excited about looking into this guideline and endorsing it. So, this was very much for a topic that we thought is very useful and very timely.

Brittany Harvey: And that's great to hear. So then, Dr. Broaddus, as an author both on the guideline endorsement and as a member of the original guideline panel, what are the key recommendations of the CAP guideline?

Dr. Russell Broaddus: So, there are six key recommendations from the College of American Pathologists guideline that ASCO recently endorsed. I like to think of the first four as being bundled together because they're interrelated - we dealt with these by cancer type for the first four. So, for colorectal cancer, there's by far the most published evidence on this type of testing, and the evidence-based guideline found that really did not matter so much whether you used immunohistochemistry, or PCR-based microsatellite instability analysis, or next-generation sequencing-based analysis to detect mismatch repair or microsatellite instability. The three different techniques are almost interchangeable in their metrics.

Similarly, for gastroesophageal adenocarcinoma and small intestinal adenocarcinoma, immunohistochemistry and PCR-based MSI are very, very similar. There's not quite enough published evidence to equate next-generation sequencing. There were one or two very, very good papers with limited number of patients. The guideline committee felt like if there was maybe one or two more published papers in this space, that for gastroesophageal adenocarcinoma and small bowel adenocarcinoma, it would be similar to colorectal adenocarcinoma, whereas the three techniques were nearly interchangeable. After that, unfortunately, the published evidence really drops off in both quantity and quality for almost all other cancer types.

So, endometrial cancer, there's quite a bit of literature. Most of it really points to the immunohistochemistry outperforms PCR-based MSI analysis and PCR-based next-generation sequencing analysis. Most likely, that's because these PCR-based approaches nearly always are optimized to detect mismatch repair defects in colorectal cancer, or other GI types of cancer. And there's actually very good published evidence that this detection of mismatch repair can be cancer-type specific. So, the recommendation is to use immunohistochemistry for endometrial cancer.

Fourth recommendation for all other cancer types not encompassed by those first three recommendations, the committee recommends to choose a laboratory-based approach to detect mismatch repair or microsatellite instability defects, but there is no good published evidence to suggest which is the best approach. And again, like with endometrial cancer, there's evidence that the PCR-based approaches, which are usually optimized for colorectal cancer and GI-type cancers, may not be sufficient to work well with cancer types outside of the GI tract. So, almost by default, the recommendation is to choose immunohistochemistry.

Fifth recommendation: Many people tend to equate microsatellite instability and high tumor mutation burden. For sure, in colorectal cancer and other GI tract cancers, these two entities, there is substantial overlap. But for cancer types outside of the GI tract, you can easily have a tumor that has a mismatch repair defect, or high levels of microsatellite instability and not have high tumor mutation burdens. So, the recommendation is to not equate those two entities.

And finally, last recommendation is that for all of us to remember that these defects in DNA mismatch repair or microsatellite instability, are also hallmarks of hereditary cancer syndrome - Lynch syndrome, and that if you identify unexpectedly that a patient with an advanced cancer has one of these defects and DNA mismatch repair, to consider the possibility of Lynch syndrome, and to alert the appropriate care team, for those patients’ family members can be screened as well.

Brittany Harvey: Understood. Thank you for reviewing those evidence-based recommendations made by the CAP panel, and then endorsed by the ASCO panel.

So, were there any additional points of discussion or emphasis raised by the ASCO endorsement panel?

Dr. Russell Broaddus: Yes. And very appropriately, I believe. One-- and this is purely because of the issue of scope, and not to minimize the importance of these issues. One issue that the CAP guideline did not address was the important issue of pre-analytic variables and how they can impact diagnostic testing. A second issue, again, not considered by the CAP evidence-based guideline group, because of just tremendous scope problems, is how do these tests - immunohistochemistry, PCR-based MSI analysis, PCR-based next-generation sequencing analysis - how do we incorporate their use with PD-L1 immunohistochemistry, for example? Liquid biopsies, as a second example. Should we have a staged approach in assessing tumors with all these different testing modalities? And frankly, the answer is, we don't know right now. I think this represents an excellent area where oncologists and pathologists can actually work to provide the evidence in some specific cancer types on whether multiple modalities provide benefit compared to just one modality.

Brittany Harvey: Definitely, those are key points perhaps for future research, and I appreciate you explaining what was in and out of scope of this guideline.

So then following that, Dr. Johnson, in your view, what is the importance of this guideline endorsement, and how will it affect ASCO members?

Dr. Tyler Johnson: I think to understand the importance of this particular endorsement, it's helpful to zoom the lens out to 30,000 feet for a minute. Pretty much, all oncologists, I think remember 10 or 12 years ago, the types of drugs that we now commonly use for immunotherapy, burst onto the scene with the treatment of melanoma. And those trials were quite remarkable because previous to that, not only did we not have a cure for metastatic melanoma, we hardly had a treatment for metastatic melanoma. We had really almost nothing to offer those patients. And then there was this, initially a small and then a larger, and then a much larger series of patients, who we now know with 10 or 12 years of follow up, that many patients who were treated with immunotherapy, who had metastatic melanoma were actually cured. Not just treated but cured.

So, in the decade or so since then, there has been this understandable and appropriate stampede of trying to figure out, "Okay, how do we use similar drugs in all of the other many metastatic tumor types?" And I think to generalize a lot, and to make overly simple a very complicated picture, what has emerged from that is that unfortunately for many metastatic solid tumors, immunotherapy just doesn't do much. It's essentially inert, as best we can tell clinically. But there is a small percentage of patients, exactly what percentage depends on the tumor type and the genetic analysis as we're talking about here, but there's a small percentage, maybe 10-20% of patients, who derive this unbelievable benefit from immunotherapy in metastatic solid tumors, to the point that some of those patients, including in other solid tumors, not just melanoma, appear to be functionally cured by the administration of immunotherapy.

And so, the question of course that has resulted from that, is if eight or nine patients are going to get no benefit and maybe even harm from administration of immunotherapy, but one or two patients out of 10 is going to get this really remarkable benefit, it would be so great if we could be much more specific in knowing which patients are going to derive benefit, and which patients are not going to derive any benefit and may even be harmed. And I think that that's the context within which we have to understand this guideline endorsement, is that this is getting us one step further to knowing which patients are likely to get benefit from immunotherapy in metastatic solid tumors.

And the really nice thing, as Russell pointed out, is that one kind of shorthand takeaway from this is that it is almost never wrong to look at the question with immunohistochemistry. And that's a great answer, because it is also almost always the most readily available test. And so, if you have a patient who has a metastatic solid tumor and you order immunohistochemistry to look for microsatellite instability, that's almost regardless of the tumor type, it's probably going to give you a reliable answer. And if it shows that they're microsatellite unstable, then that means that that patient, regardless of the tumor type, really probably should get immunotherapy upfront or very close to upfront. And then there are more nuances sort of beyond that. But I think that's really the take home message, that this gives us one powerful tool for discerning who is likely to get benefit from these therapies.

Brittany Harvey: Absolutely. That's a key thought that you just mentioned, that this is about delivering personalized medicine to individual patients.

So then, you've already touched on this a bit in your last answer, but finally, to wrap us up, how will these recommendations impact patients with cancer being considered for immune checkpoint inhibitor therapy?

Dr. Tyler Johnson: I think that many clinical oncologists have the experience that when you sit down to talk to a patient who has newly diagnosed metastatic cancer, what their treatment is going to be, almost all of them have heard about immunotherapy somewhere; in the newspaper, or from friends, or in a cancer support group or whatever. So, most of them want to know what part, if any, immunotherapy is going to play in the care of their cancer right upfront. And I think this gets us one step closer to being able to answer that question. Now, the one thing that-- and Russell touched on this a little bit, but I think it's just important to highlight, this gives us an important way to predict people who are going to respond, but that does not necessarily mean that people who this does not identify as likely responders are therefore not going to respond. And that gets into a much more complicated question that depending on the tumor type, you may have to look at PD-L1 expression, or other things. So, it's just to say that this is not a comprehensive, definitive answer, but it is one important part of the answer.

I don't know if Russell or Praveen wants to add any more thoughts about that, but that's kind of how I would contextualize this.

Dr. Russell Broaddus: I think where there's a lot of opportunity here for us to start developing the evidence on the utility or not, of such staged approaches that if-- say like, immunohistochemistry does not reveal a mismatch repair defect, should we, for some of these cancer types where we don't routinely assess PD-L1, should we next do PD-L1 immunohistochemistry? And if that doesn't show overexpression, should we next try next-generation sequencing approach? Because sometimes those don't overlap with immunohistochemistry. So, I think there's a lot of room for us to provide this evidence.

Dr. Praveen Vikas: Yeah. And one point I would like to add, we had a lot of discussion among our ASCO endorsement panel, was that by recommending IHC or PCR over NGS in certain cancer, there would be scenarios where NGS will be needed, because NGS would tell us a lot more, like HER2 amplifications, and that was our point of discussion. We wanted to make sure that we send that message that even in cases where IHC and PCR is being done, that we may still have additional need for NGS testing.

Dr. Tyler Johnson: Yeah. Thank you, Praveen, for that. I should qualify, just to make sure that it's clear, that when I said that IHC is a good go-to, I only meant in terms of testing for this specific thing.

Part of the problem with next gen sequencing is that it often takes 4-6 weeks, and so I think the practical approach is, you should send the next-generation sequencing, but in the meantime, you can do the IHC to have an answer to that particular question, and usually in one or two days, depending on the lab, and then the next gen sequencing can come back whenever it comes back, and then you can use that for directing later lines of therapy.

Brittany Harvey: Excellent. Well, I've really enjoyed this discussion today, and I want to thank you all for your work on this guideline endorsement, and thank you for your time today, Dr. Vikas, Dr. Johnson and Dr. Broaddus.

Dr. Praveen Vikas: Thanks so much, Brittany.

Dr. Russell Broaddus: Thank you.

Dr. Tyler Johnson: Appreciate the time.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast.

To read the full guideline, go to: www.asco.org/molecular-testing-and-biomarkers-guidelines.  You can also find many of our guidelines and interactive resources in the free ASCO guidelines app, available in the Apple App store or the Google Play store.

If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe, so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy, should not be construed as an ASCO endorsement.

Dr. Manish Shah discusses the first ASCO guideline for advanced gastroesophageal cancer. He addresses biomarker testing to help guide therapy - including HER2 testing, mismatch repair testing, and assessment of PD-L1 expression. Dr. Shah then reviews the evidence-based recommendations from the ASCO Expert Panel, including first-line therapies for esophageal, gastroesophageal junction (GEJ), and gastric adenocarcinoma, along with esophageal squamous cell carcinoma, based on these biomarker results, as well as evidence in the second-line setting – and beyond – and how to provide optimal care for these patients.

Read the full guideline, "Immunotherapy and Targeted Therapy for Advanced Gastroesophageal Cancer: ASCO Guideline" at www.asco.org/gastrointestinal-cancer-guidelines

TRANSCRIPT

Brittany Harvey: Hello, and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network; a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at: asco.org/podcasts.

My name is Brittany Harvey, and today, I'm interviewing Dr. Manish Shah, from Weill Cornell Medicine, in New York, New York, lead author on 'Immunotherapy and Targeted Therapy for Advanced Gastroesophageal Cancer: ASCO Guideline’.

Thank you for being here, Dr. Shah.

Dr. Manish Shah: Thank you for having me. It's great to be here, and I'm looking forward to our interview.

Brittany Harvey: Great. And first, I'd like to note that ASCO takes great care in the development of its guidelines, and ensuring that the ASCO Conflict of Interest policy is followed for each guideline. The full Conflict of Interest information for this guideline panel is available online, with the publication of the guideline in the Journal of Clinical Oncology.

Dr. Shah, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Manish Shah: Yeah. So, I've received research funding from Merck, as well as from Bristol Myers Squibb, as well as from Oncolys Pharma. These are all companies that have worked for immunotherapy and upper GI cancers.

Brittany Harvey: Okay, thank you for those disclosures.

Then diving into the content here, what is the scope and purpose of this first ASCO guideline for advanced gastroesophageal cancer?

Dr. Manish Shah: Thank you. As you point out in the question, this is the first guideline for advanced gastroesophageal cancer, and really it is a very timely guideline because the landscape for the management of upper GI cancers has evolved and changed dramatically in the last several years. For a long time, we were really focused on chemotherapy for esophagus and gastric cancer. We, in fact, treated squamous cell cancer of the esophagus very similar to adenocarcinoma of the esophagus. And even though we knew of the different disease subtypes for gastric cancer, they didn't really play a role in differentiating management.

About 10 years ago, trastuzumab was approved for the treatment of HER2-positive gastric cancer, but since then, we've had really a run of significant positive studies that have informed practice, and we felt that this was really a timely guideline to help us with regard to our patients with upper GI cancer, particularly, with metastatic disease who need first-line, and beyond therapy.

Brittany Harvey: Excellent. Then you've just mentioned that the management of these upper GI cancers has evolved, so I'd like to review the key recommendations of this guideline that you just gave an overview of. So, starting with first-line therapy - is immunotherapy, or targeted therapy in combination with chemotherapy, recommended as first-line treatment for advanced gastroesophageal adenocarcinoma or squamous cell carcinoma? And what are these recommendations by the subgroups of patients by HER2 status or PD-L1 protein expression?

Dr. Manish Shah: The answer to that is that, in fact, it is now recommended for most patients, but I think I might start a little bit one step behind. So, with a newly diagnosed patient with an upper GI cancer, I think the first step in the management is to test for the biomarkers that will help guide therapy. So, for esophageal adenocarcinoma gastroesophageal junction, and gastric cancer, which is almost always adenocarcinoma, we recommend that everybody undergo HER2 testing immunohistochemistry, as well as a mismatch repair testing or MSI-high; either way you get it is fine, as well as an assessment of the PD-L1 expression, which is scored according to the Combined Positive Score or CPS.

So, that panel of biomarkers will help guide the management for the adenocarcinomas. And so, if you are HER2-positive, then we've known for a long time that the standard of practice would be chemotherapy with trastuzumab; typically, it's a platinum and 5-FU-based treatment with trastuzumab. Most recently, and this is in the guideline and the second part of your question, if you're HER2-positive, and you actually now are recommended to do chemotherapy with trastuzumab and pembrolizumab, which is a PD-1 inhibitor. Then that's based on the KEYNOTE-811 study, that we have the first analysis, which is a response rate analysis, and the response rate improves significantly with the addition of the immunotherapy.

But for the majority of patients who are HER2-negative, we do look at the PD-L1 status by CPS, then here it's a little bit trickier. The FDA guidance is to recommend immunotherapy with chemotherapy for all patients in the first-line setting. However, we also recognize that the higher the PD-L1 expression, the more likely the benefit from immunotherapy. And several studies have demonstrated that, and we've shown that in the guideline as well.

And there seems to be a very reasonable cutoff of a CPS score of five or higher, and above that, there really is clear benefit of the addition of immunotherapy, specifically, nivolumab to chemotherapy for gastroesophageal cancer, that's based on CheckMate 649. And then for esophageal adenocarcinoma, the additional recommendation is the addition of chemotherapy with pembrolizumab for a CPS of 10 or higher. And I think for CPS zero, most of us really felt pretty strongly that there was really no role for the use of immunotherapy because remember, these drugs do have some side effects, that although rare, can be really debilitating.

And then, there's an intermediate category of CPS, 1-4, and here, I think you have to use a little bit of a judgment call. We didn't recommend it in general but did suggest that that would be more of an individual-use basis. And the judgment call is that if the CPS is four, if you showed the slides to another pathologist, it's very possible it could have been a five. So, that kind of heterogeneity is something that we might consider to go ahead and use the immunotherapy.

But if the CPS is lower, the context is also questionable. We talked a little bit about the side effects of immunotherapy. If someone really has bad rheumatoid arthritis, we've all actually had patients given immunotherapy, they come in debilitated. So there, we really would want to be sure that the CPS is high, so that way, the patient is deriving the benefit, and we then adjust the rheumatoid arthritis medicines accordingly.

So, I think the other theme through our guideline is that with more options, we are able to actually provide more personalized care to our patients, giving them the best opportunity to receive the care with minimizing toxicity and maximizing benefit. So, that was a long-winded answer to the question that we do recommend immunotherapy in the first-line setting, in the right context, and for HER2-positive tumors, we recommend trastuzumab plus immunotherapy in the first-line setting, in the right context.

And then, the final thing was the mismatch repair status. So, unlike colon cancer where there's level one evidence comparing immunotherapy to first-line chemotherapy, we don't have that in upper GI cancers. So, we do recommend it, but as for the guidance, it would be in the second-line setting, or later.

Brittany Harvey: Great. Those are key clinical considerations that you just reviewed, and I appreciate you talking through both the evidence, and then the discussions that the panel had on the benefits of therapy, and also the adverse effects that can affect patients.

So, then, beyond first-line therapy for later-line therapies, is immunotherapy or targeted therapy recommended as second-line or third-line treatment for advanced gastroesophageal adenocarcinoma?

Dr. Manish Shah: Yeah. This is a great question, and I think it can be a point of confusion. So, for a long time, immunotherapy, specifically pembrolizumab, was approved and indicated in the third-line setting for CPS 1 or higher patients. The FDA actually removed that approval, and so it's no longer indicated in that setting. And most patients will have gotten immunotherapy in the first-line setting, and as of now, there's no data that suggests that continuing immunotherapy or rechallenging with immunotherapy would be of any benefit.

So, in general, the answer is that we would not use immunotherapy beyond first line. I guess the one caveat is if your CPS is low and you didn't receive immunotherapy in the first-line setting, but you happen to be MSI-high, then certainly, that would be an indication to use immunotherapy in that setting. But I think that would be a pretty rare event. So, if you use immunotherapy in the first-line setting, then there's really no role for continuing or re-challenging with immunotherapy in the second or later-line settings. But that's an active area of drug development, and we think that there will be an opportunity in the next few years for combination strategies to salvage people who had immunotherapy in the first-line setting.

So, in terms of second line and beyond, the other area that we should talk about is in squamous cell cancer. So, squamous cell cancer is a little bit unique, of the esophagus. It is more sensitive to immunotherapy than adenocarcinoma, and in fact, the guidance is to use immunotherapy, either with chemotherapy or as a doublet nivolumab and ipilimumab, in the first-line setting for most patients with squamous cell cancer. If, however, immunotherapy wasn't used in the first-line setting for squamous cell cancer, it is indicated in the second-line setting as nivolumab monotherapy. So, that would be one distinction between the squamous esophageal cancer and adenocarcinoma of the upper GI tract.

Brittany Harvey: Great. I appreciate you reviewing those considerations for later-line therapies, and we'll look forward to more research in this area in the future, as you just described.

Thank you for reviewing all of those recommendations. In your view, what is the importance of this guideline, and how will it impact clinical practice?

Dr. Manish Shah: So, this is an important guideline, because as we've talked earlier, there are lots and lots of options for patients, and we think that the guideline will help frame the discussion on how to best manage our patients in the first line, second line, and beyond.

I think it also frames where there are holes in our knowledge. These knowledge gaps are opportunities for research, for us to continue to develop therapies in gastroesophageal cancers.

Brittany Harvey: So, that's excellent. And you just mentioned that there's more options for patients with advanced upper GI cancers. So, finally, Dr. Shah, how will these guideline recommendations affect patients with advanced gastroesophageal cancer?

Dr. Manish Shah: Yeah. I hope that it will give patients and their physicians a strategy for how to treat patients in the first-line and beyond setting. Gastroesophageal cancer treatment has evolved significantly. Not too long ago, there was a debate of whether or not chemotherapy had a benefit in the first-line setting, or in the second-line setting, and there are randomized studies that demonstrate that for sure. Now, we're in an era where people should get chemotherapy, and then in the right context, get additional targeted agents, like immunotherapy or HER2-targeted therapy.

And if we can treat patients along the continuum of their care, thinking about first line, second line, third line, much as we do for colon cancer, we think that more patients will be able to get access to more of the drugs that are available, and in the long run, that will ultimately help more patients, and give patients better outcomes. I hope this guideline will achieve that goal for our community.

Brittany Harvey: Absolutely. And I appreciate you providing the details and the context for this new guideline. Thank you so much, for all of your work to develop these evidence-based recommendations. And thank you for your time today, Dr. Shah.

Dr. Manish Shah: Oh, absolutely. Thanks so much for having me, and I'm happy to come back anytime.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series.

To read the full guideline, go to: www.asco.org/gastrointestinal-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available on iTunes or the Google Play Store.

If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe, so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy, should not be construed as an ASCO endorsement.

Dr. Dwight Owen presents the first update to the ASCO living guideline on stage IV NSCLC with driver alterations. He identifies the latest trials that informed this update, and the updated evidence-based options for second- or later-line therapies for patients with advanced non-small cell lung cancer and an activating HER2 mutation or a KRAS-G12C mutation. Additionally, he provides important context on the reported toxicities associated with these therapeutics.

Read the update, “Therapy for Stage IV Non–Small-Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2022.2“ and view all recommendations at www.asco.org/living-guidelines. Listen to Part 1 for recommendations for patients with stage IV NSCLC without driver alterations.

TRANSCRIPT

Brittany Harvey: Hello, and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network; a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at: asco.org/podcasts.

My name is Brittany Harvey, and in our last episode, we addressed the living guideline updates for ‘Therapy for Stage IV Non-Small-Cell Lung Cancer Without Driver Alterations.' Today, Dr. Dwight Owen from Ohio State University in Columbus, Ohio, is joining us again to discuss the updates for therapy for stage IV non-small cell lung cancer with driver alterations, as the lead author on, 'Therapy for Stage IV Non–Small-Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, version 2022.2.'

Thank you for being here, Dr. Owen.

Dr. Dwight Owen: Thanks for having me.

Brittany Harvey: First, I'd like to note the ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest policy is followed for each guideline. The full Conflict of Interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology.

Dr. Owen, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Dwight Owen: Yeah, thanks for asking that really important question. My institution has received research funding for me to conduct clinical trials from Merck, BMS, Pfizer, and Genentech and Palobiofarma. I have no employment, stocks, stock options, or other disclosures to declare.

Brittany Harvey: Thank you for those disclosures. Then getting into the content of this update, this is the first update to the living clinical practice guideline for systemic therapy for patients with stage IV non-small-cell lung cancer with driver alterations. What new studies were reviewed by the panel to prompt an update to this guideline?

Dr. Dwight Owen: Thanks for that question. This is a particularly exciting update because as we were preparing for this update, reviewing two manuscripts that we think offer new options for our patients with driver alterations, there were actually updated presentations at a recent meeting that showed us even more data for these targets. So, it's really an ongoing and dynamic place. So, we really focused on two updates; one was for KRAS-G12C alterations, and then one was for HER2 alteration-positive non-small cell lung cancer.

So, I'll take them one at a time; for KRAS-G12C, we included an updated recommendation based on the CodeBreak 100 study - this was a multi-center, single group, open-label, phase II study of sotorasib, which is a KRAS-G12C inhibitor, in patients with non-small cell lung cancer positive for KRAS-G12C, who had received prior systemic therapy that could either be with chemotherapy or immune therapy, and the majority of patients had received both. 124 patients were evaluable for response, and the objective response rate was 37%, with the impressive median overall survival of over 12 months, of 12.5 months, specifically.

Now, there were some notable toxicities. There's GI toxicities such as diarrhea and nausea, as well as some elevations in LFTs. We also heard recently at ESMO about CodeBreak 200, which was a randomized study of sotorasib compared to docetaxel in previously treated patients with KRAS-G12C non-small cell lung cancer. And that study did meet its primary endpoint of improvement in PFS for sotorasib-treated patients compared to docetaxel, and we are very much looking forward to seeing that final publication.

For HER2 alteration-positive non-small cell lung cancer, we really focused our efforts on DESTINY-Lung01. Now, this was a multi-center, multinational, open-label, phase II study evaluating trastuzumab deruxtecan in patients with previously treated HER2-positive non-small cell lung cancer. In this study, 91 patients were evaluable for response, and 50, which was 55%, had a confirmed objective response, and the median survival was presented at 17.8 months.

A pretty unique toxicity was observed here. So, drug-related interstitial lung disease or pneumonitis occurred in just over a quarter of patients, and there were two deaths related to this. So, this needs to certainly be monitored for. Also at ESMO, we heard results for DESTINY-Lung02, which was a multi-center, multi cohort, randomized blinded study, which was also a dose optimization study. And this study eventually led to the accelerated approval of the 5.4 milligrams per kilogram dose that seemed to be just as effective as other doses, but perhaps with less toxicity. Again, we're currently awaiting the final publication of DESTINY-Lung02. However, these results are particularly impressive and especially leading to the FDA accelerated approval for a new treatment option for our patients with HER2 alteration positive non-small cell lung cancer.

Brittany Harvey: I appreciate you reviewing that data and the new updates for both of these drugs and targets in this population.

So then, I'd like to review the recommendations that the panel updated for our listeners. First, what is the new recommendation for patients with advanced non-small cell lung cancer and in activating HER2 mutation?

Dr. Dwight Owen: So currently, these patients should continue to receive standard first-line treatment as we do not have head-to-head trials for HER2-directed therapy in the first line. However, for patients who have previously received systemic therapy and have a HER2-activating mutation, trastuzumab deruxtecan certainly should be offered to these patients.

Brittany Harvey: Understood. And then the second category of patients that you identified, what does the expert panel recommend for patients with advanced non-small cell lung cancer and a KRAS-G12C mutation?

Dr. Dwight Owen: So, similarly, these patients should continue to receive standard first-line treatment, as we do not have head-to-head trials for KRAS-directed therapy in the first line. However, for patients who have previously received systemic therapy and have a KRAS-G12C mutation, sotorasib can be offered as a subsequent therapy. Keep in mind that this is only approved in patients with the KRAS-G12C mutation, and not other KRAS alterations.

Brittany Harvey: Thank you for reviewing those two recommendations for second or later-line therapies. What should clinicians know as they implement these updated recommendations?

Dr. Dwight Owen: So, I think what we're really excited about is that both of these agents offer new treatment options for patients who historically did not have a personalized targeted treatment option. We are awaiting publication of additional studies to help interpret these data, but for now, clinicians should discuss these treatment options with their patients, and also keep in mind the pattern of toxicities that seem to be unique to each treatment.

Brittany Harvey: Great. And then, you've just addressed some of this in your last response, but what does this change mean for patients with stage IV non-small lung cancer with a HER2 or KRAS-G12C mutation?

Dr. Dwight Owen: I think the bottom line is that our patients for whom their cancer does not respond, or where it progresses after first-line treatment, will now have additional effective and approved treatment options that are really tailored to the unique characteristics of their tumor and cancer cells.

Brittany Harvey: Absolutely. It's great to have new options for patients in this field.

So then finally, are there future research developments that the panel is considering for future living guideline updates?

Dr. Dwight Owen: So, we're particularly looking forward to the final publication of the studies that were recently presented, including the CodeBreak 200, and DESTINY-Lung02 trials. There are multiple ongoing studies for additional targets, including in the targets that we talked about; so, KRAS-G12C as well as HER2, as well as a number of other targeted options that may benefit subsets of our patients with metastatic non-small cell lung cancer.

Brittany Harvey: Great. Well, I appreciate you reviewing all this data and the updated recommendations, and thank you for your time today, Dr. Owen.

Dr. Dwight Owen: Thanks for having me.

Brittany Harvey: And thank you to all of our listeners for tuning into the ASCO Guidelines podcast series. To read the full guideline, go to: www.asco.org/thoracic-cancer-guidelines.  There's a companion living guideline update on therapy for stage IV non-small-cell lung cancer without driver alterations, available there and in the JCO.

You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available on iTunes, or the Google Play store.

If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy, should not be construed as an ASCO endorsement.

Dr. Dwight Owen presents the first update to the ASCO living guideline on stage IV NSCLC without driver alterations. He reviews the new evidence identified by the panel along with the updated recommendation regarding the role of bevacizumab in pemetrexed maintenance therapy. Dr. Owen also discusses exciting trials the panel is looking forward to seeing results of to drive future updates to the living guidelines.

Read the update, “Therapy for Stage IV Non–Small-Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2022.2“ and view all recommendations at www.asco.org/living-guidelines. Listen to Part 2 for recommendations for patients with stage IV NSCLC with driver alterations.

TRANSCRIPT

Brittany Harvey: Hello, and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network; a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at: asco.org/podcasts.

My name is Brittany Harvey, and today I'm interviewing Dr. Dwight Owen, from Ohio State University in Columbus, Ohio, lead author on, 'Therapy for Stage IV Non-Small-Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, version 2022.2.'

Thank you for being here, Dr. Owen.

Dr. Dwight Owen: Thanks very much, Brittany, for having me.

Brittany Harvey: First, I'd like to note the ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest policy is followed for each guideline. The full Conflict of Interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology.

Dr. Owen, do you have any relevant disclosures that are directly related to the guideline topic?

Dr. Dwight Owen: I have research funding to my institution to conduct clinical trials from several companies, including Merck, Pfizer, Genentech, BMS, and Palobiofarma, but no ownership, no stock, and no employment history.

Brittany Harvey: Okay, Thank you for those disclosures.

Then let's get into the content of this living guideline update. So, this is the first update to the living clinical practice guideline for systemic therapy for patients with stage IV non-small cell lung cancer without driver alterations. What new evidence was identified by the routine literature searches to prompt an update to the guideline?

Dr. Dwight Owen: Yeah, so this is a really exciting time for patients with stage IV non-small cell lung cancer. We are anxiously awaiting the results of some ongoing immunotherapy combination studies. However, for this update, we focused on a specific paper and study that evaluated a treatment that is not our first option anymore, but maybe the first option for a subset of patients.

So, before the standard introduction of immunotherapy for patients with stage IV non-small cell lung cancer, we often offered platinum-based doublet chemotherapy, and for years, we studied ways to make that better. So, we might introduce maintenance therapy where we continue a treatment after the first line of induction chemotherapy. We did either continuation maintenance, which is where you continue a treatment that seemed to be effective, or switch maintenance, where you were introduced to new therapy.

For many folks with non-squamous non-small cell lung cancer, the standard treatment options included carboplatin or cisplatin with pemetrexed, which is an antifolate chemotherapy, or carboplatin and paclitaxel with or without a VEGF inhibitor, such as bevacizumab. One of the big questions was whether there was a benefit for continuing maintenance therapy with something besides pemetrexed, in this case, bevacizumab, and if bevacizumab was given in combination with pemetrexed, whether continuing that as a maintenance would offer benefit.

Now, it's important to point out that the current FDA approval, at least in the United States, is for bevacizumab to be given with carboplatin and paclitaxel. However, several studies looked at the combination with pemetrexed and there were several issues with those studies. So, in one study they used a different agent, so ramucirumab instead of bevacizumab, both VEGF, but slightly different. In one study, the combination that was compared of pemetrexed plus bevacizumab was only compared to bevacizumab maintenance. And so, we really had a sort of hodgepodge of different trials that never answered the question of whether bevacizumab or VEGF therapy, given as maintenance offered any benefit to our patients.

What Dr. Garon and co-authors did in a study that we evaluated was conduct a meta-analysis of four of those randomized trials, focusing on the question of comparing pemetrexed maintenance therapy alone versus in combination with bevacizumab. And what they found is that there was no significant difference in overall survival with the addition of bevacizumab compared to pemetrexed by itself, and there were higher rates of toxicity in those patients, including serious and higher-grade toxicities.

So, I felt that it was really important to point out that the addition of bevacizumab or other VEGF therapies does not seem to add to a survival benefit when given as maintenance. And even though this is a subset of patients who perhaps could not get immunotherapy as a first-line treatment, maybe because of a pre-existing autoimmune disorder, but for those patients, it doesn't seem that the addition of VEGF as maintenance offers what we were hoping for.

Brittany Harvey: Understood, and I appreciate you laying out the landscape of the data in this area. So then, based off this new data and the meta-analysis that you just described, what is the updated recommendation from the expert panel?

Dr. Dwight Owen: So, the updated recommendation is a tweak to the established recommendation, which is essentially that for patients who are not candidates for immunotherapy for any reason, that platinum doublet chemotherapy is really the mainstay, and that if maintenance is offered, that it should not include VEGF therapy in combination with pemetrexed as compared to pemetrexed by itself.

Brittany Harvey: Understood. And then, what should clinicians know as they implement this updated recommendation?

Dr. Dwight Owen: I think, again, this should be a relatively uncommon scenario. Most of our patients are candidates for immune therapy. Many patients are offered platinum pemetrexed by itself. But when thinking about continuing maintenance therapy, we would recommend that most clinicians avoid the addition of therapies that haven't seemed to offer a survival benefit and incur higher rates of toxicity.

Brittany Harvey: Great. That's helpful to know. And then you've just mentioned that this doesn't apply to a lot of patients, but what does this change mean for patients with stage IV non-small cell lung cancer without driver alterations?

Dr. Dwight Owen: I think, hopefully, for the subset of patients where we're really thinking about here that we can at least avoid additional toxicity if there isn't a trade-off in terms of benefit, in terms of survival.

Brittany Harvey: Great. Definitely, that's helpful. And then finally, what ongoing research is the panel keeping an eye on for future living guideline updates?

Dr. Dwight Owen: So, there are a lot of exciting trials that are ongoing, and hopefully, we'll be able to read out soon, that would offer us updates for really how to manage these patients in the frontline setting with stage IV non-small cell lung cancer. We have multiple options now. This discussion that we've had today really focuses on the pre-immunotherapy era, but of course, bevacizumab is utilized in a regimen along with carboplatin, paclitaxel, and atezolizumab, compared to monotherapy with checkpoint inhibitors compared to chemoimmunotherapy and dual checkpoint inhibitors.

And we don't really have any head-to-head trials yet, or strategies on how to identify which patients need more aggressive combination therapies versus which patients could potentially do without chemotherapy, or with single-agent checkpoint inhibitor by itself. So, while we wait for those studies like the ECOG and Cigna study, we're really looking forward to having those to be able to help decide and tailor our treatment options for our patients.

Brittany Harvey: Great. Well, we'll look forward to the ongoing review of the literature by the panel and any future guideline updates to recommendations in the meantime.

So, thank you so much for your work on this update and thank you for your time today, Dr. Owen.

Dr. Dwight Owen: Thanks for having me.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series.

To read the full guideline, go to: www.asco.org/thoracic-cancer-guidelines. There's also a companion living guideline update on Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations, available there and in the JCO.

You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes, or the Google Play store.

If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy, should not be construed as an ASCO endorsement.

Dr. Emrullah Yilmaz reviews the latest evidence and recommendations for health care providers on biomarker testing and immunotherapy for head and neck cancers. He discusses the ASCO Expert Panel’s recommendations for biomarkers for the selection of patients with head and neck squamous cell carcinoma for anti-PD-1 immune checkpoint inhibitor therapy. Additionally, he reviews recommended treatment options, including first-line treatment based on PD-L1 status, therapies for platinum-refractory disease, options for patients with nasopharyngeal cancer, the role of radiation therapy for oligometastatic head and neck cancer, and immunotherapy for rare head and neck cancers. Dr. Yilmaz also explores future areas of research for therapeutic options for patients with head and neck squamous cell carcinoma.

Read the full guideline, “Immunotherapy and Biomarker Testing in Recurrent and Metastatic Head and Neck Cancers: ASCO Guideline” at www.asco.org/head-neck-cancer-guidelines.

TRANSCRIPT

Brittany Harvey: Hello, and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network; a collection of nine programs, covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at: asco.org/podcasts.

My name is Brittany Harvey, and today I'm interviewing Dr. Emrullah Yilmaz, from Cleveland Clinic in Cleveland, Ohio, lead author on, 'Immunotherapy and Biomarker Testing in Recurrent and Metastatic Head and Neck Cancers: ASCO Guideline’.

Thank you for being here today, Dr. Yilmaz.

Dr. Emrullah Yilmaz: Thank you so much.

Brittany Harvey: Then first, I'd like to note that ASCO takes great care in the development of its guidelines, and ensuring that the ASCO Conflict of Interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology.

Dr. Yilmaz, do you have any relevant disclosures that are directed related to this guideline topic?

Dr. Emrullah Yilmaz: No, I don't have a relevant disclosure.

Brittany Harvey: Thank you. Then let's dive right into this guideline.

So, generally, what is the purpose and the scope of this guideline?

Dr. Emrullah Yilmaz: Immunotherapy with anti-PD-1 immune checkpoint inhibitors has become one of the most important treatment options for patients with recurrent metastatic head and neck cancers. And in the last few years, there has been new studies leading to new indications such as combinations with chemotherapy, or single-agent immunotherapy in the first-line treatment. And moreover, several studies also shown the effectiveness of immunotherapy for patients with nasopharyngeal carcinoma. All these advances in this complex disease group made it necessary to have an evidence-based guideline. So, that was the basis of building this guideline.

Brittany Harvey: Understood. And then this evidence-based guideline addresses six clinical questions. So, I'd like to review the key recommendations for each of those questions for our listeners. So, let's start with the first question. What did the expert panel recommend regarding biomarkers for selecting patients with head and neck squamous cell carcinoma for anti-PD-1 immune checkpoint inhibitor therapy?

Dr. Emrullah Yilmaz: Biomarkers are key for selection of treatment for immunotherapies, especially for the first-line treatment for head and neck cancer patients. PD-L1 is measured by immunohistochemistry and reported as Combined Positive Score, CPS, or Tumor Proportion Score, TPS. CPS is slightly different than TPS, and it includes lymphocyte and macrophage PD-L1 expression, in addition to tumor cells. Head and neck cancer studies have shown that CPS is a better marker for predicting response to immune checkpoint inhibitors, and key head and neck trials started to use CPS for reporting PD-L1 status. Therefore, we recommend CPS for recurrent metastatic head and neck cancers for PD-L1 reporting. This also makes it important for the oncologists to have a communication with the pathologists to make sure the right PD-L1 scoring is reported for head and neck cancer patients. Tissue tumor mutation burden is another emerging biomarker when CPS is not available, or for rare head and neck tumors, tumor mutation burden can be used as a biomarker as well.

Brittany Harvey: Great. And then based on that PD-L1 status that you just mentioned, what is the optimal first-line treatment regimen for patients with recurrent or metastatic head and neck squamous cell carcinoma?

Dr. Emrullah Yilmaz: If PD-L1 is positive, which is CPS more than one, there are two different options. Both pembrolizumab, single agent or pembrolizumab plus chemotherapy with platinum and 5-Fluorouracil can be offered. KEYNOTE-048 study showed an overall survival benefit with pembrolizumab alone for patients with CPS more than one, which was greater for the patients with CPS 20 or more. However, the pembrolizumab plus chemotherapy has showed benefit for the patients regardless of the PD-L1 status. So, if an early response is needed for a patient with high disease burden, pembrolizumab with chemotherapy could be an option, even if the PD-L1 is positive. For patients with negative PD-L1, which is CPS less than one, we recommend pembrolizumab and chemotherapy.

There was a recent subgroup analysis of KEYNOTE-048 for CPS-low patients. Patients with CPS less than one subgroup did not have significant survival difference with pembrolizumab plus chemotherapy when compared to cetuximab plus chemotherapy. This included a small number of patients, and this study was not powered to look at this subgroup, but cetuximab and chemotherapy can also be considered in the PD-L1 negative patient.

Brittany Harvey: Understood. It's important to recognize which patients benefit from these treatments more than others in different subgroups. So, following that, what is the effect of immunotherapy compared to other systemic treatments in platinum-refractory recurrent, or metastatic head and neck squamous cell carcinoma?

Dr. Emrullah Yilmaz: Platinum-refractory disease is defined as recurrence within six months of platinum-based chemotherapy. And effectiveness of immunotherapy was actually proven in this disease group first, several years ago. The effectiveness of immunotherapy as a single agent was proven in two similarly designed phase III trials in this setting. CheckMate 141 trial compared nivolumab to standard-of-care methotrexate, cetuximab, or docetaxel, and KEYNOTE-040 trial compared pembrolizumab to similar standard-of-care agents. And both studies showed overall survival benefit when compared to standard-of-care systemic agents, and the responses were independent from the PD-L1 expressions. So, nivolumab or pembrolizumab, are options as single-agent immunotherapy treatments for the patients with platinum-refractory head and neck squamous cell carcinoma, regardless of their PD-L1 expression.

Brittany Harvey: Understood, and thank you for getting into those options for those patients. Getting into the specifics for nasopharyngeal carcinoma, what did the panel recommend regarding the role of immunotherapy for patients with recurrent or metastatic nasopharyngeal carcinoma?

Dr. Emrullah Yilmaz: So, the combination of immunotherapy with cisplatin and gemcitabine was shown to be effective in first-line treatment of recurrent metastatic nasopharyngeal carcinoma, in several phase III studies from Asia in the last few years. JUPITER-02 study used toripalimab, CAPTAIN-1 study used camrelizumab, and RATIONALE-309 study used tislelizumab in combination with cisplatin and gemcitabine in the first-line treatment, and all these studies showed progression-free survival benefit with addition of immunotherapy to chemotherapy.

Since these agents are not available in the United States as of now, our panel members recommend that pembrolizumab or nivolumab may be offered in combination with chemotherapy for the first-line treatment of recurrent or metastatic nasopharyngeal carcinoma. But the role of immunotherapy in the platinum-refractory nasopharyngeal carcinoma without the prior immunotherapy use is not well established yet. There are phase II studies that have shown that responses to immunotherapy are comparable to chemotherapy with a better safety profile. So, single-agent immunotherapy could be considered in a platinum-refractory setting if a PD-1 inhibitor was not used before.

Brittany Harvey: Those are excellent points that you just made. So, following that, the next question that the panel considered is, what is recommended regarding the use of radiation therapy in combination with immunotherapy versus immunotherapy alone, for the treatment of locoregionally recurrent or oligometastatic head and neck squamous cell carcinoma?

Dr. Emrullah Yilmaz: This is a great question, and radiation therapy is used a lot in head and neck cancers for different purposes. And immunotherapy and SBRT combinations were not shown to increase efficacy for abscopal effect for the treatment of oligometastatic disease in head and neck cancers. So, radiation therapy should not be given to increase the effectiveness of immunotherapy in recurrent metastatic head and neck cancers. However, there are several ongoing studies to evaluate the efficacy of radiation such as SBRT with immunotherapy for locoregional recurrence. So, although radiation therapy is safe to give the patients with recurrent and metastatic cancers, with immunotherapy, it should be considered for palliation or local control until the results of these trials are available.

Brittany Harvey: Great. And yes, we'll look forward to the results of those trials to find some more definitive results for these patients. So, then, the last clinical question that the panel addressed, what is recommended for the role of immunotherapy for rare head and neck cancers?

Dr. Emrullah Yilmaz: The role of the immunotherapy for rare head and neck cancers depends on the biomarkers. KEYNOTE-158 study has shown the effectiveness of pembrolizumab in advanced cancer patients, which included different types of cancers with high tissue TMB defined as more than 10 mutations per megabase. And looking at the results from that study for the patients with advanced rare head and neck cancers with limited treatment options, such as, salivary gland cancers or sinonasal cancers, if high TMB, which is Tumor Mutational Burden, is identified, then pembrolizumab may be considered for those patients. And pembrolizumab was also shown to have activity in salivary gland cancer patients expressing more than 1% PD-L1. So, that makes it an option for these patients as well.

Brittany Harvey: It sounds like understanding the biomarker status of these patients with rare head and neck cancers is essential for determining their therapy options. I want to thank you so much for reviewing all of those recommendations.

So, in your view, Dr. Yilmaz, what is the importance of this guideline, and how will it impact clinicians and patients with head and neck squamous cell carcinoma?

Dr. Emrullah Yilmaz: This guideline was written by panel members, experts in their field, including medical oncologists, radiation oncologists, head and neck surgeons, pathologists, and radiologists. It is really important for oncologists to communicate the treatment options to their patients clearly while planning treatment of head and neck cancers. So, this guideline can help the clinicians to provide evidence-based resource when to use the immunotherapy for their head and neck cancer patients. So, that can be really helpful to the clinicians.

Brittany Harvey: Excellent. Yes, it's important to have a multidisciplinary group working on these guidelines to help clinicians in all capacities.

Finally, what outstanding questions or ongoing research are you interested in for future therapeutic options in head and neck squamous cell carcinoma?

Dr. Emrullah Yilmaz: Our guideline focuses on recurrent metastatic head and neck cancers since it is the only area where the immunotherapy is approved as of now. We've had a few studies in the curative intent setting, which has not shown the benefit of addition of immunotherapy to radiation therapy, or chemoradiation. There's still several studies ongoing to investigate the effectiveness of immunotherapy in the curative intent setting, and the neoadjuvant setting, or adjuvant setting, or different combinations with the radiation therapy, with the immunotherapy, with the different sequences. So, it will be interesting to see the results of those studies in the future. So, that might be another area that the field might be moving in the future.

There are also studies ongoing to improve effectiveness of the immunotherapy in the recurrent and metastatic disease. Chemoimmunotherapy seems to be among the strongest systemic treatment options right now that we have, but there are several other combination strategies that are being developed combined with the PD-1 inhibitors, including combinations with EGFR inhibitors, angiogenesis inhibitors, intratumoral injections, vaccine developments, and there are a lot of different novel checkpoint inhibitors being developed. So, the field is advancing in that area as well. So, those are the areas that research are ongoing at this point.

Brittany Harvey: Definitely. We'll look forward to the results of those ongoing trials to inform future updates and future guidelines in this area.

So, I want to thank you so much for all of your work that you put into developing these evidence-based guidelines and thank you for your time today, Dr. Yilmaz.

Dr. Emrullah Yilmaz: Thank you so much.

Brittany Harvey: And thank you to all of our listeners for tuning to the ASCO Guidelines podcast series. To read the full guideline, go to: www.asco.org/head-neck-cancer-guidelines.

You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in iTunes or the Google Play Store.

If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe, so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy, should not be construed as an ASCO endorsement.

Dr. Judith Paice and Dr. Eduardo Bruera discuss the latest evidence-based recommendations from ASCO on the use of opioids in managing cancer-related pain. They review the safe and effective use of opioids, including when clinicians should offer opioids, which opioids should be offered, how opioids should be initiated and titrated, management of opioid-related adverse events, modifying opioid use for patients with specific comorbidities, management of breakthrough pain, and how opioids should be switched. Additionally, they address barriers to care, considerations of health disparities, cost, and patient-clinician communication in achieving optimal pain management.

Read the full guideline, “Use of Opioids for Adults with Pain from Cancer or Cancer Treatment: ASCO Guideline” at www.asco.org/supportive-care-guidelines.

TRANSCRIPT

Brittany Harvey: Hello, and welcome to the ASCO Guidelines Podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts.

My name is Brittany Harvey, and today, I'm interviewing Dr. Judith Paice from Northwestern University Feinberg School of Medicine in Chicago, Illinois and Dr. Eduardo Bruera from the University of Texas MD Anderson Cancer Center in Houston, Texas, co-chairs on “Use of Opioids for Adults with Pain from Cancer or Cancer Treatment: ASCO Guideline.”

Thank you for being here, Dr. Paice and Dr. Bruera.

Dr. Judith Paice: Thank you.

Dr. Eduardo Bruera: Thank you for having us.

Brittany Harvey:  First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline.

The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Paice, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Judith Paice: I have no relevant disclosures.

Brittany Harvey:  Thank you. And then Dr. Bruera, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Eduardo Bruera: Regrettably, I don't.

Brittany Harvey: Great. Then getting into the content of this guideline, to start us off, Dr. Paice, can you provide an overview of the purpose and the scope of this guideline?

Dr. Judith Paice: The use of opioids has become so complicated, so controversial, and just so associated with so much stigma that we wanted to provide oncology clinicians some guidance about safe and effective use of opioids.

We wanted to help people be aware of the current literature, and so we conducted a systematic review and identified randomized controlled clinical trials and other systematic reviews. And we found that there were 31 systematic reviews in 16 RCTs.

We carefully reviewed all of these literature and all of these studies, and our expert panel met via the web and via numerous conference calls and emails, and we came to consensus regarding these recommendations related to the use of opioids for people with cancer.

Brittany Harvey: Great. Sounds like there was a lot of effort that went into developing this and to tackle an important topic.

So, then Dr. Bruera, I'd like to review the key recommendations of this guideline for our listeners. This guideline addresses seven different clinical questions. So, let's review these questions starting with; in what circumstances should opioids be offered?

Dr. Eduardo Bruera: That's a very important point because the reality is that although opioids have been around for more than 300 years in different modalities, they continue to be the mainstay of care of patients with severe pain.

So, it's very important to try to figure out in the clinical practice why the patient has a pain syndrome. But in the great majority of patients who have pain that is due to the presence of the primary cancer or metastatic disease.

And also, in the vast majority of patients who develop severe complications from treatment such as mucositis from radiation and chemotherapy, an opioid will be needed. And the oncologist and the oncology clinician is in perfect conditions to safely prescribe that opioid so the patient can achieve fast relief of their pain.

Brittany Harvey: Great. Thank you for that explanation. So, then the next clinical question that the panel addressed, Dr. Paice, which opioids does the panel recommend clinicians should offer?

Dr. Judith Paice:  Yeah, thank you. This is a really important question, one that gets asked all of the time, and yet, the data are insufficient to really suggest that there is one preferred opioid over another.

So, a patient with moderate to severe cancer-related pain is a candidate for any of the approved medications either approved by the FDA or because our audience also includes international experts, other regulatory agencies for pain treatment. We did call out a couple agents for which there is some concern or for issues where they are less than desirable in some settings.

So, one of those drugs is tramadol. And our rationale for identifying tramadol as a potential agent of concern is that it's a prodrug. It has a threshold, a ceiling unlike most of the other opioids, and that threshold is pretty low for neurotoxicity, which is of particular concern in the person with cancer. And it also, has a significant amount of drug-drug interactions.

So, we were concerned about tramadol, even though it is an agent that many, many people are using, in part, because it is a lower schedule on the controlled substance scheduling system, and there's a perception that it is less potent, and it is less potent.

The other drug that we call out is codeine. And our rationale for identifying it as an agent that may be of difficulty in certain populations of patients, is that it is also a prodrug and it is metabolized through the cytochrome P450 system, particularly through the isoenzyme CYP2D6. And that's what allows codeine to be metabolized to morphine, which allows it to be analgesic.

The challenge is there are some individuals who are poor metabolizers, and so they will not receive an analgesic effect. And then there are others who are ultra-rapid metabolizers, and they may actually experience a greater prevalence of adverse effects. So, for those reasons, we call out tramadol and codeine.

Now, we don't call out methadone as an agent that we're concerned about in terms of not being desirable. It is an agent that has a role in cancer pain management. However, we do caution clinicians that it is a complex drug to use.

And so, as result, people should obtain some guidance either from their palliative care program, their supportive care program, pain experts, or pharmacists, whomever can assist them in the dosing associated with this really important, but somewhat complicated drug to use.

Brittany Harvey: Understood. And I appreciate you reviewing where there's a lack of evidence and where there is evidence in identifying those potential agents of concern or where clinicians need to seek other expertise in this area.

So, then following those recommendations, after identifying patients who should be offered opioids, Dr. Bruera, how should opioids be initiated and titrated?

Dr. Eduardo Bruera: One possible way to do this is to give the patient an immediate release opioid. That could be a combination of hydrocodone with acetaminophen, a combination of other opioids or a straight strong opioid in a low concentration.

And ideally, we suggest that you use it as needed for the first few days and see if the patient needs to take it frequently. And there is a magic number around 30 milligrams of morphine equivalent per day.

Once the patient needs to take that opioid on a more frequent basis and gets through that threshold of needing about five, six tablets a day of immediate release opioid, then it might be necessary to start a regular opioid that is to stay on top of the pain.

And the way we do that are two ways; if the patient can afford it and insurance covers it, an extended release opioid is a wonderful option, because then, the patient can take the opioid a couple of times a day or put a patch for three days and they're going to be comfortable.

But if that is not an option, taking the immediate release opioid around the clock, not anymore as needed. But now, around the clock, will maintain that blood level and allow the patient to have less episodes of breakthrough pain.

An important thing to remember is that whether we decide to go with the extended release opioid or immediate release, it's nice to tell the patient that there might be moments in which the pain might break through. And so, giving that extra prescription and advice might help if there are moments in which the patient might break through.

Brittany Harvey: Understood. And then the next clinical question that the guideline panel addressed, Dr. Paice, how should opioid-related adverse events be prevented or managed?

Dr. Judith Paice: So, Brittany, I'm glad you asked me that question because I am called the pain and the poop nurse in the clinic, and it is so important whenever we can to prevent the adverse effects of opioids, and constipation is one where we can implement some preventive measures, and then treat unfortunately if your measures have not been totally effective.

But we wanted to address the gamut of potential adverse effects. So, we included not only constipation, but delirium, endocrinopathies, sedation, nausea, vomiting, itching, and urinary retention.

And we've included a table with very specific suggestions about how to prevent in some cases, and how to manage these adverse effects. Again, we wanted to make this document of the most use for all oncology clinicians who might be prescribing opioids for people with cancer.

Brittany Harvey: Absolutely. And that's key to maintaining quality of life for patients. So, then Dr. Bruera, what does the panel recommend regarding modifying opioid use in patients with either renal or hepatic impairment?

Dr. Eduardo Bruera: That's a great question, Brittany, and I think we have some evidence that some opioids are particularly desirable when the patient has renal dysfunction.

One of the ones that comes to mind is methadone because it has almost no major renal elimination, and therefore, that might be a wonderful option. One of the challenges is that changing from one opioid to another sometimes is a little bit more complex than maintaining the opioid that is being used.

And so, in absence of a major and fast deterioration, one option is to carefully titrate the dose of the opioid we’re using to reduce the risk of accumulation in a given patient.

There are some opioids that have traditionally been associated with a little bit more accumulation in cases of renal failure and traditionally, morphine is included, but there are other opioid agonists that also produce metabolites that are massively eliminated by urine that might be a little bit less desirable in patients with renal failure.

With regards to liver failure, it's very hard to find a complete consensus about the opioids that are less desirable or potentially more desirable. And we could say that careful titration is important.

But the one that was so good for renal failure might be the one you might not want to use for liver failure, and that would be methadone, because a vast majority of its metabolism happens in liver.

So, I think cautious individualized titration might be a nice recommendation to our patients. And perhaps, the most important thing is that there might be a little bit of renal failure or liver failure, but it's very, very important that we maintain the opioid therapy, that we don't give up on the opioids.

Brittany Harvey: Yes, those are important clinical considerations for individualized patient care. So, then Dr. Paice, Dr. Bruera touched on this a little bit earlier, but what are the recommendations regarding management of breakthrough pain?

Dr. Judith Paice: So, breakthrough pain is very common in the person with cancer. We see this when the individual has bony metastases and they place pressure on that limb or joint. And the patient who's normally well-controlled with either a regularly scheduled immediate release agent or a long-acting agent, now experiences what we call breakthrough.

And that's probably the most common type of breakthrough pain. There are also other breakthrough pains where the short-acting agent that's given regularly doesn't provide the relief that lasts four hours or six hours. Or similarly, if a long-acting agent is given every 12 hours, we may see that the pain breaks through prior to the next dose.

But for that patient who requires breakthrough medication, unfortunately, the literature does not reveal that one agent is superior to another. So, any immediate release opioid that's appropriate for that patient can be used for breakthrough-related pain.

Now, a common clinical conundrum is - which dose? What's the correct dose for the breakthrough medication? And again, the literature has a wide range of appropriate doses, and our committee established a range of 5 to 20% of the daily regular oral morphine equivalent daily dose.

And our rationale for that was that you really cannot come up with one figure. Every patient is different. So, on average it's somewhere around 10%, but the range is five to 20% of the daily regular morphine equivalency.

And so, what you need to do as you're examining the patient and exploring their needs is to look at the patient's frailty, the patient's pain, of course, their function when these breakthrough episodes occur. What about the comorbid kinds of organ dysfunction that Eduardo just spoke about?

So, all of those other factors need to be considered when selecting the appropriate opioid for the breakthrough as well as the appropriate starting dose.

Brittany Harvey: Definitely, it's important to consider all of those factors that you just mentioned. So, then the last clinical question that the panel addressed, Dr. Bruera, when and how should opioids be switched or rotated?

Dr. Eduardo Bruera: Thank you, Brittany. This is a hugely important issue because for many, many years, we believe that since opioids stimulated an opioid Mu receptor, and they all had a similar effect, there will be limited rationale for changing.

The answer to increasing pain was what we call opioid dose escalation. Just give more of the same. And we realized that that had serious limitations. And one of them is the development of side effects. And a lot of those side effects are neurotoxic side effects.

Patients get unduly sedated, get hyperalgesia, paradoxical increase in pain due to active metabolites and changes in their receptors, and they also get sometimes myoclonus, hallucinations, confusion.

And so, there are moments in which the side effects require us to say, okay, this opioid has done a good job for a while, but now, we have to change. And so, changing can be done due to side effects.

But also, sometimes, since we're all different and there's a lot of interpersonal variation in response — as some patients may just not be controlled, their pain syndrome might not be controlled well-enough with one type of opioid because we know there are multiple sub-Mu receptors, and they might really benefit from another.

So, the two main reasons are the development of toxicity to the opioid that so far was working reasonably well. And the second is failure, inability to control the pain, and in that case, going cautiously respecting the fact that there is limited cross-tolerance so that the dose of one opioid is not always exactly equivalent to the dose of the other opioid that you find in the actual tables that are published around is necessary to understand that that's a general guideline.

But the most important thing is to go progressively and monitor your patient frequently when you change from one opioid agonist to another opioid agonist.

There is limited understanding in the literature about the exact equianalgesic dosing. And because of that, a new guideline is being produced that addresses opioid rotation and deals exactly with trying to find out consensus from all the different existing tables on how to change what is the dose that is most likely to be appropriate when you move from one opioid, for example, morphine to hydromorphone or to fentanyl, or to oxycodone or vice versa.

We dealt with great trepidation to give all our oncology clinicians some kind of a fixed table, but the evidence is unfortunately not there at this point. It is sad because these medications are not that new, but the evidence unfortunately, is not there.

And that's why I think what we can tell you is go through your guidelines, use in a very careful monitoring of your patient to see if the dose you're giving is clearly not enough or it's a little bit too much. And you will learn that very rapidly — in a couple of days, you'll learn if you're doing okay or if you're doing too much or not enough.

And stay tuned because hopefully, very soon, ASCO, together with MASCC and a couple of other organizations will provide you with a little bit more evidence around this.

Brittany Harvey: Definitely, we'll look forward to that future guideline on opioid conversion tables as it is a confusing and complicated area, but it sounds like a lot of these recommendations are about providing individualized care for your patients.

So, I want to thank you both for reviewing all of those recommendations that the panel came up with.

So, then Dr. Paice, what does this guideline mean for both clinicians and for patients with pain from cancer or their cancer treatment?

Dr. Judith Paice: Well, speaking on behalf of the panel, our wish is that this will improve the management of cancer-related pain, that people will feel more comfortable in safe and effective use of these agents, and they'll be used more effectively.

There are other barriers that we've addressed, in addition to all of these recommendations. We talk about the care of people who have multiple chronic conditions. We address the disparities that we see in cancer pain management, and we talk about cost as another consideration, as one is developing a treatment plan for patients.

We also address the patient-clinician communication that is so essential. This is definitely a team effort, and we guide our clinicians and offer for patients the need to have clear communication, open dialogue throughout the development of a treatment plan, and then throughout the course of treatment while we reassess whether the plan has been effective.

Brittany Harvey: Absolutely. And it's really key what you just said about the safe and effective use of opioids for patients.

So, then finally, Dr. Bruera, you've both mentioned this throughout our conversation today, where the literature is either inconclusive or evidence is insufficient. So, what are the outstanding questions about the use of opioids for pain from cancer or cancer therapies?

Dr. Eduardo Bruera: I think there are questions that relate to the relative lack of specificity of the opioids for the different receptor pathways, and there are very likely considerable differences because they're chemically quite different, but they're considerable differences.

But we have not done an awful lot of the head on comparisons that would be so wonderful to do. And I think we need more studies comparing the different existing medications, and more importantly, we need a lot of translational work to get to specific areas.

Wouldn't it be fantastic if we were able to stimulate the Mu receptor all along the nociceptive pathway to reduce nociceptive input, but avoid completely the limbic system and avoid those Mu receptors in the area where reward is going to happen, an anti-reward and the possibility of developing non-medical use and eventually, opioid use disorder.

That would be, to me, the corollary, the ability to dissociate those receptors along the nociceptive pathway from those receptors in the areas where we would like our opioids to not go, but we cannot avoid it because they're a bit dummy drugs. And so, hopefully, getting smarter opioids would be wonderful.

Brittany Harvey: Absolutely. Well, I want to thank you both so much for your work developing this guideline, addressing these important questions for optimal pain management in patients with cancer. And thank you for your time today, Dr. Paice and Dr. Bruera.

Dr.  Judith Paice: Thank you.

Dr. Eduardo Bruera:Thank you so much.

Brittany Harvey:And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast series. To read the full guideline, go to www.asco.org/supportive-cancer-guidelines.

You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play Store.

If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

Voiceover: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy, should not be construed as an ASCO endorsement.

An interview with Dr. Van Morris from The University of Texas MD Anderson Cancer Center in Houston, TX and Dr. Cathy Eng from Vanderbilt-Ingram Cancer Center in Nashville, TN, co-chairs on "Treatment of Metastatic Colorectal Cancer: ASCO Guideline." Dr. Morris and Dr. Eng review the evidence-based recommendations from the guideline, focusing on areas of uncertainty in the treatment of metastatic colorectal cancer, and highlighting the importance of multidisciplinary collaboration and shared decision-making between patients and clinicians. Read the full guideline at www.asco.org/gastrointestinal-cancer-guidelines.

TRANSCRIPT

Brittany Harvey: Hello, and welcome to the ASCO Guidelines Podcast series, brought to you by the ASCO Podcast Network; a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at: asco.org/podcasts.

My name is Brittany Harvey, and today I'm interviewing Dr. Van Morris, from The University of Texas MD Anderson Cancer Center in Houston, Texas, and Dr. Cathy Eng from Vanderbilt-Ingram Cancer Center in Nashville, Tennessee - co-chairs on, 'Treatment of Metastatic Colorectal Cancer, ASCO Guideline.'

Thank you for being here, Dr. Morris, and Dr. Eng.

Dr. Cathy Eng: Thank you.

Dr. Van Morris: Thank you.

Brittany Harvey: First. I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest policy is followed for each guideline. The full Conflict of Interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology.

Dr. Morris, do you have any relevant disclosures that are directly related to the guideline topic?

Dr. Van Morris: Not personally, but I do have research support to my institution from Pfizer and Bristol Myers Squibb who have products that I'll be discussing on this podcast.

Brittany Harvey: Thank you, Dr. Morris. And Dr. Eng, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Cathy Eng: Also, not personally associated with any honorarium specific to this topic.

Brittany Harvey: Great. Thank you both. So then, let's talk about the content of this guideline. So first, Dr. Morris, can you provide an overview of the scope of this guideline?

Dr. Van Morris: Sure. So colorectal cancer is the second-leading cause of cancer-related death in the United States. And especially in the time of the recent COVID-19 pandemic with people less likely to go for screening colonoscopies, there's great concern that more and more patients will be presenting at the time of their initial diagnosis with later-stage, more advanced colorectal cancer. So with that said, research is moving very quickly for the benefit of patients with colorectal cancer, and we were interested in assembling a multidisciplinary team that consisted of medical oncologists, surgical oncologists, radiation oncologists, pathologists, and radiologists as well, to help us make guidelines that really summarize the most relevant up-to-date practices, based on rigorous literature review for treatment recommendations for advanced metastatic colorectal cancer.

Brittany Harvey: Great. And then as you just mentioned, this guideline provides recommendations, and a lot of those focus on areas of uncertainty in the treatment of metastatic colorectal cancer. And I'd like to review those key recommendations that you mentioned for our listeners.

So, Dr. Eng, starting with - for patients with previously untreated, initially unresectable metastatic colorectal cancer, who are candidates for chemotherapy plus bevacizumab, is doublet or triplet cytotoxic chemotherapy recommended?

Dr. Cathy Eng: For treatment-naive patients, bevacizumab has been approved, and we do agree that it's a very reasonable treatment option with doublet or triplet therapy for our patient population. Obviously, these are guidelines, and it's extremely important to keep in mind that as a provider, you need to discuss the potential side effects with the patient. With bevacizumab, you know, standard concerns must be discussed with the patient, especially in regards to wound healing, if they've had recent surgery or any potential risk factors for a recent cardiac event from a recent thrombosis. So, those things obviously, would preclude the patient from initiating treatment with bevacizumab. But currently, doublet therapy or triplet therapy could be a potential option for patients.

Brittany Harvey: Great. And yes, as you mentioned, shared decision-making is paramount to these decisions.

So then following that recommendation, Dr. Morris, which patients should be offered pembrolizumab in the first-line setting?

Dr. Van Morris: Yeah. So, I think that this represents really one of the exciting advances in the treatment of metastatic colorectal cancer over the past several years. We have great data now that suggests for patients with microsatellite instability-high metastatic colorectal cancer, especially who have not had any prior treatment, we would recommend use of immune checkpoint blockade therapies, really coming from the seminal KEYNOTE-177 trial. This was a phase III international trial that looked at patients with advanced unresectable or metastatic colorectal cancer. And patients were either randomized to pembrolizumab monotherapy, or cytotoxic chemotherapy with FOLFOX, with or without bevacizumab. And this trial did meet its primary endpoint and showed an improvement in progression-free survival, with use of pembrolizumab as a single agent relative to cytotoxic chemotherapy. And based on this trial and the clear benefit that we see in patients with pembrolizumab, the FDA has approved this as an option for patients with MSI-high untreated metastatic colorectal cancer.

There are other trials which have looked at use of immunotherapy; the CheckMate 142 trial looked at combination PD-1 CTLA-4 therapy as a single-arm study. And, you know, there's another trial, the CheckMate 8HW, which is looking at one versus two immunotherapy agents in this setting as well. But really, as it stands for now, patients with MSI-high untreated metastatic colorectal cancer are the ones who benefit from the use of immunotherapy.

One of the questions that we often get in talking with other clinical oncologists is the FDA approval for pembrolizumab in any cancer type for a TMB, tumor mutation burden, greater than 10. And, we talked about this with our panel in this context, and we don't see that patients with microsatellite-stable metastatic colorectal cancer, who have a tumor mutation burden over 10 benefit from use of immunotherapy. There is one exception to this for patients who harbor pathogenic POLE or POLD1 mutations, these patients oftentimes do experience sustained clinical benefit with immunotherapy. But in general, patients with microsatellite-stable metastatic colorectal cancer, who don't have POLE/POLD1 mutations, we don't favor use of immunotherapy in that context at this point in time.

Brittany Harvey: Great. Thank you for reviewing that recommendation and the data behind who benefits and who doesn't benefit from immunotherapy in this setting.

So then following that, the next question that this guideline addressed is for treatment-naive RAS-wild type metastatic colorectal cancer. So, for these patients, Dr. Eng, is anti-EGFR therapy recommended for patients with right or left sided primary tumors?

Dr. Cathy Eng: That is such an important question, and thank you for asking this. We know based upon pivotal data from CALGB/SWOG 80405, that right-sided tumors treatment-naive, even if they're RAS-wild type, these patients should not receive anti-EGFR therapy. But also, we've learned from 80405, FIRE-3, and PEAK, which was a phase two study, that there appeared to be some benefit versus anti-VEGF therapy for left-sided tumors based upon studies that have been conducted.

So, at this year's ASCO, actually, the PARADIGM trial was specifically a phase III trial, more focused on left-sided tumors. It was amended twice before it decided to focus on the left-sided patient population. And it was a phase III study where patients were randomized to FOLFOX plus panitumumab versus FOLFOX and bevacizumab. And the primary endpoint was overall survival. And we added this data to our guidelines. This data just came out, hot off the presses in June, at this year's ASCO. And the primary endpoint was fulfilled. And basically, it prospectively demonstrated that the data from the other three trials, based upon a pooled analysis, suggested left-sided tumors fare better with anti-EGFR therapy. And in fact, the PARADIGM trial basically validated those findings. Obviously, the PARADIGM trial just recently presented, we have not seen the final publication, we do not know much about the maintenance setting, but specifically, when thinking about anti-EGFR therapy, it is very reasonable to consider it in a left-sided tumor, all RAS-wild type patient population.

I would like to mention though, and we do highlight this also in the guidelines, which is critically important, is that there was another study, which is a phase III trial called, TRIPLETE, that was presented as well, looking at FOLFOXIRI plus panitumumab versus basically, standard treatment. And what it noted is that there is no additional benefit for FOLFOXIRI plus panitumumab in left-sided tumors in regards to response or progression-free survival, there was no additional benefit. So, FOLFOX plus panitumumab seems very reasonable, FOLFOXIRI plus panitumumab is not necessarily needed in left-sided tumors.

Brittany Harvey: Great. Thank you for that explanation, and also for the work of the panel to rapidly include this new information recently presented at ASCO.

So then following those recommendations, Dr. Morris, what recommendation did the panel make for patients with previously-treated metastatic colorectal cancer with a BRAF V600E mutation?

Dr. Van Morris: Yeah. So, this recommendation was made essentially based on one randomized phase III clinical trial, which reported out about three years ago now, the BEACON trial. This is looking at patients with BRAF V600E mutated metastatic colorectal cancer, which we know accounts for probably eight to 10% of all patients with advanced colorectal cancer, and when found, really harbors a poor prognosis relative to BRAF-wild type counterparts.

So, the BEACON trial was a trial that looked at patients with previously-treated metastatic colorectal cancer, who have BRAF mutations, either kind of standard of care cytotoxic chemotherapy, or a BRAF/EGFR combination with encorafenib and cetuximab or alternatively, a BRAF/EGFR/MEK combination. That trial showed that improvement in survival outcomes with a BRAF/EGFR-targeted approach, as well as the BRAF/MEK/EGFR. However, because there was no difference in survival with the addition of the MEK inhibitor, the FDA subsequently approved encorafenib and cetuximab as the recommended treatment for patients with BRAF V600E previously-treated metastatic colorectal cancer. Because the MEK combination with binimetinib was not recommended by the FDA, you know, we did not include that analysis in our guidelines for ASCO. But as it stands right now, we do strongly encourage all clinicians to check for their BRAF V600E mutation status in their patients with metastatic colorectal cancer, with the goal of getting them to a targeted therapy approach over their treatment course.

Brittany Harvey: Great. Thank you for providing that information.

So, following that, Dr. Eng, what are the recommendations for patients with colorectal peritoneal metastases?

Dr. Cathy Eng: The current recommendations for colorectal cancer with peritoneal disease, really, there's no strong evidence to support the role of heated intraperitoneal chemotherapy. We now know based upon the literature from one of the largest studies to date, the PRODIGE data, demonstrating that there may be some potential benefit from cytoreductive surgery for the patients in regards to overall survival. But these patients are at high risk for bowel obstruction, potentially for perforation, and obviously, quality of life is an issue. So, these patients should always be discussed in a multidisciplinary tumor board whenever possible, and hopefully, to meet with a surgeon that is more experienced, specifically, in treating peritoneal disease, because these patients do require a lot of multidisciplinary care and discussion. So currently, based upon the existing data, we don't recommend heated intraperitoneal chemotherapy, but there may be a role for cytoreductive surgery.

Brittany Harvey: Thank you, Dr. Eng for going over those recommendations.

So then following that, Dr. Morris, for patients with unresectable liver-limited metastatic colorectal cancer, which liver-directed therapies are recommended?

Dr. Van Morris: So, this is I think a really good question and one that just like the prior question with regards to peritoneal surgery, is one that we felt was a challenging one, but a common one that we wanted to address. And specifically, I think this is an example of where level of evidence comes into the strength of recommendation.

So, for patients with unresectable liver-limited metastatic colorectal cancer, we looked at the questions of, "What is the role of SBRT - stereotactic body radiotherapy, and what is the role of SIRT, which is selective internal radiotherapy?" And for both of these, we felt that the level of evidence was weak, and I think that it's very important to make note of that in assessing the recommendations.

But to start with, for SBRT, we looked at one meta-analysis for patients with oligometastatic colorectal cancer, and also analyzed 18 non-randomized control trials in this setting. Most of the patients in these studies had one to five liver metastases, with the majority having one or two liver metastases. From the meta-analysis, we saw kind of a one-year local control rate of around 67%, a two-year control rate of 59%. So, based on those and recognizing the limitations of non-randomized trials and making recommendations, the panel did feel that it was reasonable to consider use of SBRT for oligometastatic colorectal cancer. The SABR-COMET trial is one that had looked at the role of radiotherapy for treatment of oligometastatic colorectal cancer, and I just want to make the point as well, that we did not include that in our analysis or recommendations at this point in time, because this really didn't include a lot of patients with colorectal cancer that we felt warranted inclusion.

Now, with regards to SIRT, we looked at kind of one meta-analysis and three randomized control trials for patients with mostly liver-limited metastatic colorectal cancer. All patients had liver disease, but there were about 40% of the patients we looked at in the meta-analysis, had extra hepatic disease as well. In the frontline setting, there really was no difference in progression-free survival or overall survival with the use of SIRT. And more recently, we've seen in a second-line trial, it was called the EPOCH trial, reported several years ago, this looked at patients with previously-treated metastatic colorectal cancer in the second-line setting. Patients were randomized to either chemotherapy with, or without transarterial radioembolization with Y90.

While there was an improvement in overall response rate, there was no meaningful improvement in overall survival with the use of SIRT. But there were significant increases in grade 3 or grade 4 toxicities when SIRT was added to chemotherapy. So, kind of given this, we didn't feel at this point in time that SIRT should be recommended for patients with metastatic colorectal cancer. Although, again, I do want to highlight that really these discussions should be happening at high-volume centers, kind of with a multidisciplinary group of clinicians.

Brittany Harvey: Definitely. And thank you for highlighting that multidisciplinary collaboration.

And the last section of recommendations, Dr. Eng, what is recommended for patients with metastatic colorectal cancer, and potentially-curable oligometastatic liver metastases?

Dr. Cathy Eng: So, another controversial topic. And once again, this is why we decided to include this as part of the guidelines, because this is a common scenario where patients are potentially curable, following liver resection for oligometastatic disease. We cannot highlight enough the importance of multidisciplinary discussion. Prior data has not been strong regarding specific guidelines following liver resection. We do recommend that based upon the existing data, there is no level one evidence to say, you should go one way or another following metastatic resection, and whether or not adjuvant therapy is warranted in that setting. But we do recommend multidisciplinary management and engagement and discussion. So, although it's not definitive, it basically suggests that there is a role for resection. It does provide improved five year survival relative to systemic chemotherapy, if the patient is potentially resectable, but does require multidisciplinary discussion. And it is a shared decision-making process.

Brittany Harvey: Great. Thank you. And I appreciate you highlighting the importance of shared decision-making throughout this guideline.

So then, Dr. Morris, what is the importance of this guideline in your opinion, and how will it impact clinical practice?

Dr. Van Morris: Yeah. So, I think that we understand that management of metastatic colorectal cancer is extremely complex given the various molecular annotations and the multimodality therapies which are possible for our patients. So, we tried to limit the guidelines here to include what we feel are the most recent updates, but also kind of the most clinically-relevant multidisciplinary questions that get asked for treatment of metastatic colorectal cancer. We also recognize that things are changing quickly. And for example, we didn't decide to include at this point in time, management of HER2 neu amplified metastatic colorectal cancer, although we are seeing more and more data coming out, suggesting targeted therapies. So, I think it's important for clinicians to realize that these are guidelines which are ever-changing, given the updates with new therapies available for our patients.

And the other thing I think that's very good about these guidelines is that, even though we may be making recommendations about controversial topics in the management of metastatic colorectal cancer - specifically, I think the use of HIPEC with cytoreductive surgery, locally-directed therapies to the liver, and the role of perioperative chemotherapy and metastasectomy - I think it's important for oncologists to realize that these recommendations come with varying strengths of level of evidence and that we as oncologists should be considering the level of evidence that's out there when making recommendations that affect our patients as well. So, we really wanted to support these guidelines and recommendations and empower clinicians to know and understand the quality of evidence that exists in the management of patients with metastatic colorectal cancer.

Brittany Harvey: Excellent. And yes, those are key points on the level of evidence and the strength of recommendations throughout the guideline.

And then finally, Dr. Eng, you've talked a bit about shared decision-making and the importance of this guideline for patients. So, how will these guideline recommendations affect patients with metastatic colorectal cancer?

Dr. Cathy Eng: The reason that we created these guidelines is to help patients, their caregivers, and providers, learn of the most recent developments in colorectal cancer, and the best approach based upon the information that we have personally reviewed with our multidisciplinary team of faculty members that participated in this exercise. We really just want to make sure that patients do get optimal care. And we hope that these guidelines also will help provide a foundation for some of the clinical trials that may be under development, or for other clinical trials that are being considered. So, we really just want to provide the most up-to-date information to all individuals that are interested in colorectal cancer so we can help guide their care better.

Brittany Harvey: So, I want to thank you both so much for your work on these guidelines, and all of the time it's spent developing these recommendations, and thank you for your time today, Dr. Morris, and Dr. Eng.

Dr. Van Morris: Thank you.

Brittany Harvey: And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast series. To read the full guideline, go to: www.asco.org/gastrointestinal-cancer-guidelines.

You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe, so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy, should not be construed as an ASCO endorsement.

An interview with Dr. William Tew from Memorial Sloan Kettering Cancer Center in New York, NY, lead author on "Poly(ADP-Ribose) Polymerase Inhibitors in the Management of Ovarian Cancer: ASCO Guideline Rapid Recommendation Update." Dr. Tew reviews changes to the recommendations for PARPi therapy for patients with epithelial ovarian cancer, and the outstanding questions in the field. For more information, visit www.asco.org/gynecologic-cancer-guidelines.

TRANSCRIPT

An interview with Dr. Surendra Shastri from the University of Texas MD Anderson Cancer Center in Houston, TX, and Dr. Jose Jeronimo from the National Cancer Institute in Bethesda, MD, co-chairs on "Secondary Prevention of Cervical Cancer: ASCO Resource-Stratified Guideline Update." Dr. Shastri and Dr. Jeronimo review the updated recommendations in the guideline, covering screening, triage, management, follow-up, and considerations for special populations. Read the full guideline at www.asco.org/resource-stratified-guidelines.

TRANSCRIPT

An interview with Dr. Rohan Garje from Miami Cancer Institute in Miami, FL, lead author on "Systemic Therapy Update on 177Lutetium-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer: ASCO Rapid Recommendation." Dr. Garje reviews the new evidence and the latest recommendation update for the use of 177Lu-PSMA-617, a radioligand therapy in patients with PSMA-positive mCRPC, along with it's implications for clinicians and patients. For more information, visit www.asco.org/genitourinary-cancer-guidelines.

TRANSCRIPT

Brittany Harvey: Hello, and welcome to the ASCO Guidelines Podcast series, brought to you by the ASCO Podcast Network; a collection of nine programs, covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one at: asco.org/podcasts.

My name is Brittany Harvey, and today I'm interviewing Dr. Rohan Garje from Miami Cancer Institute in Miami, Florida, lead author on, ‘Systemic Therapy Update on 177Lutetium-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer: ASCO Rapid Recommendation’.

Thank you for being here, Dr. Garje.

Dr. Rohan Garje: Absolutely. Thank you so much for having me, Brittany.

Brittany Harvey: Great. And first, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest policy is followed for each guideline. The full Conflict of Interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology.

Dr. Garje, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Rohan Garje: Yes. I have received institutional research funding from Pfizer, Amgen, Endocyte, and AAA, who have drugs for the treatment of prostate cancer.

Brittany Harvey: Excellent. Thank you for those disclosures.

Then getting into the content of this guideline update, what prompted this rapid update to the ‘ASCO Guideline on Systemic Therapy in Men with Metastatic Castration-Resistant Prostate Cancer’, which was previously published in 2014?

Dr. Rohan Garje: Since 2014, there are several new drugs that have been approved for prostate cancer management. And most recently in March 2022, FDA has approved 177Lutetium-PSMA-617 for patients with PSMA scan-positive metastatic castration-resistant prostate cancer. This led to the team from ASCO to develop this new rapid recommendation update. Now, this approval actually has been based on the efficacy data published in VISION clinical trials.

To give you a little background about Lutetium, it is a novel β-energy-emitting radioligand therapy. In this particular study, this agent was combined with best standard of care, and compared to best standard care alone, in men with metastatic castration-resistant prostate cancer, who had a positive PSMA scan. Briefly, the study was both clinically and statistically positive, and has shown improvement in both overall survival and radiographic progression-free survival. The median overall survival was about 15.3 months with the combination therapy, compared to 11.3 months with the standard care arm.

Brittany Harvey: Great. And then based off this new evidence and the new approval from the FDA for 177Lutetium-PSMA-617, what are the updated recommendations from the guideline panel?

Dr. Rohan Garje: The panel recommends the use of 177Lutetium-PSMA-617 as a treatment option in patients with PSMA PET/CT positive metastatic castration-resistant prostate cancer, who have been previously treated with at least one line of androgen receptor pathway inhibitor, and at least one line of prior taxane-based chemotherapy.

Brittany Harvey: Great. And then, what should clinicians know as they implement the use of this drug and this new recommendation by the guideline panel?

Dr. Rohan Garje: A very good question. It is important to select patients based on a positive PSMA scan. That is, all the metastatic lesions should be positive on the PSMA scan, and there should not be any large lymph nodes or visceral organ metastatic disease that are PSMA negative. Additionally, physicians can use Gallium 68 PSMA-11, or F-18 piflufolastat as radiotracers for PSMA scan to determine eligibility.

Additionally, there are several other factors that need to be considered, such as: the patient should have baseline good blood counts, as well as renal function to be eligible for this therapy, as this treatment has a potential to cause myelosuppression and impairment of renal function. The most common side effects associated with this drug are fatigue, dry mouth, dry eyes, and nausea. The treatment in general is for four to six cycles. Each cycle is for every six weeks. The fifth and sixth cycles should be considered only if patients are responding well to the therapy and have no significant toxicities.

It is also important for the physicians to note that there are several additional treatment options for patients with metastatic castration-resistant prostate cancer, who had prior anti-androgen docetaxel therapy. They include; cabazitaxel, PARP inhibitors for patients who have mutations in DNA repair, gene mutations such as BRCA1 and BRCA2, and immunotherapy with pembrolizumab for patients with MSI-high status, or tumor mutation burden greater than 10.

Brittany Harvey: Thank you for describing that nuance behind the recommendations. So then, in addition, how does this update impact patients with metastatic castration-resistant prostate cancer?

Dr. Rohan Garje: 177Lutetium-PSMA-617 is the first radioligand therapy approved for the treatment of prostate cancer. Previously, we had Radium-223 as a radiopharmaceutical, but this particular agent is unique in the sense, it is a radioligand therapy where it is chelated to PSMA. So, it is very targeted therapy which works for both bone and visceral organ metastasis. So, this is an exciting treatment option for patients, as it has been shown to have improvement in overall survival. This adds to the current treatment choices of anti-androgens, chemotherapy, as well as targeted therapies for prostate cancer patients.

Brittany Harvey: Great. It's exciting to have a new treatment option for patients.

So then finally, what are the outstanding questions regarding systemic therapy for metastatic castration-resistant prostate cancer?

Dr. Rohan Garje: We are at an exciting stage in the management of prostate cancer. In the last decade, we have seen several new drugs; some are specific targeted agents, some are specific immunotherapy agents. Now, we are entering into this realm of radioligand therapy, which is very exciting. There are several other novel radioligand therapies such as; actinium, thorium, lead, which are being evaluated in the treatment of prostate cancer. So, in the next several years, we will see several new drugs that have been developed.

In addition, there are other agents called T-cell-engaging therapies, which are being evaluated to improve the outcomes. So, the last decade definitely has seen a lot of new improvements, but we are so excited that several new treatment choices are now available for patients, and several are in clinical evaluation. So, the future is bright for the patients with prostate cancer, where we have several new treatment choices to improve their outcomes.

Brittany Harvey: It sounds like an exciting time for developments in prostate cancer.

So, I want to thank you so much for your time today, Dr. Garje, and thank you for all of the work you did to update this guideline.

Dr. Rohan Garje: Thank you so much. I really thank ASCO leadership and the team for giving me this opportunity, and thank you, Brittany, for hosting me on this podcast.

Brittany Harvey: And thank you to all of our listeners for tuning into ASCO Guidelines Podcast series. To read the full guideline, go to: www.asco.org/genitourinary-cancer-guidelines. 

You can also find many of our guidelines and interactive resources in the free ASCO guidelines app, available in iTunes or the Google Play store.

If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe, so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy, should not be construed as an ASCO endorsement.

An interview with Dr. Jun Mao from Memorial Sloan Kettering Cancer Center in New York, NY, lead author on "Integrative Medicine for Pain Management in Oncology: SIO-ASCO Guideline." Dr. Mao reviews the recommendations on integrative approaches, such as acupuncture, yoga, reflexology, massage, guided imagery with progressive muscle relaxation, hypnosis, and music therapy for managing pain in patients with cancer, and the evidence behind these recommendations. He also addresses the implications for clinicians and patients as well as outstanding questions about the use of integrative approaches for pain management. Read the full guideline at www.asco.org/survivorship-guidelines.

TRANSCRIPT

Brittany Harvey: Hello, and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcast.

My name is Brittany Harvey, and today I'm interviewing Dr. Jun Mao from Memorial Sloan Kettering Cancer Center in New York, New York, lead author on ‘Integrative Medicine for Pain Management in Oncology: Society for Integrative Oncology and American Society of Clinical Oncology Guideline’.

Thank you for being here, Dr. Mao.

Dr. Jun Mao: Thank you, Brittany. It's great to be here.

Brittany Harvey: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available in line with the publication of the guideline in the Journal of Clinical Oncology.

Dr. Mao, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Jun Mao: No, I don't.

Brittany Harvey: Great. Then I'd like to get into the content of this guideline. So what is the purpose and scope of this joint SIO-ASCO guideline?

Dr. Jun Mao: So Brittany, about one in two cancer patients or survivors experience pain that often are not adequately controlled by conventional medications. So often individuals seek out complementary and alternative medicine, more recently known as integrative medicine, for the relief of pain, but there's a very little synthesized information for oncologists to help guide the patients in choosing evidence-based integrative therapy approach. Therefore, we decided to really do a systematic review and come up with a system of guidelines that can help oncologists and patients make informed decisions about choosing the right type of integrative medicine approaches to manage pain.

The Society for Integrative Oncology and the American Society of Clinical Oncology joined forces that really convene a group of panelists, that represent many fields in conventional oncology in support of integrative medicine. And after reviewing over 200 articles from clinical trials to systematic review have come up with very thoughtful recommendations to help patients and physicians to provide the best evidence-based care on how to manage pain for patients with cancer.

Brittany Harvey: Excellent. And yes, it's great to have SIO and ASCO join forces on this guideline. So then next, I'd like to review those key evidence-based recommendations of this guideline that you just mentioned. The recommendations are provided in the guideline by pain type. So I'd like to review each category for our listeners, starting with: what is recommended for patients experiencing aromatase inhibitor related joint pain?

Dr. Jun Mao: So we recommend acupuncture should be offered to patients experiencing aromatase inhibitors related joint pain in breast cancer. And this is really evidence-based, benefits outweigh the harms. And with intermediate quality of evidence and moderate strength of recommendation. As many of our audience would know, aromatase inhibitors cause very severe types of joint pain that not only affect quality of life and functions, but make many women stop taking these life saving drugs.

So the panelists want to recommend this therapy based on large randomized control trial that hope this can be part of a pain management strategy along with exercise and duloxetine so give people the options so that women can not only have better quality of life, but also hopefully they can stay on aromatase inhibitor to prevent the recurrence of breast cancer. And we also found some weak evidence for yoga to improve joint pain related to AIs. However, the evidence is weak, although the benefit outweighs the harm. So clearly, more studies are needed to make yoga as a part of therapies for cancer patients.

Brittany Harvey: Understood. And thank you for reviewing the level of evidence behind those two interventions for patients experiencing aromatase inhibitor related joint pain. So following those recommendations, what is recommended for patients experiencing general cancer pain or musculoskeletal pain?

Dr. Jun Mao: So in terms of general cancer pain or musculoskeletal pain, there are three therapies that we consider that may be offered to patients experiencing this type of pain: acupuncture, reflexology or acupressure, or massage. So reflexology and acupressure use the same kind of principles like acupuncture, but instead of using needles, by using hands. So that's kind of in between acupuncture and  massage. So these are evidence based recommendations with benefits outweigh harms, and the quality of evidence is intermediate with moderate level of evidence and recommendations. So clearly, for cancer patients or survivors that experience this type of general cancer pain or musculoskeletal pain, I think these approaches may be appropriately integrated along with conventional pharmacotherapy or physical therapy.

Brittany Harvey: Definitely. It's great to have options to go along with conventional pharmacologic therapy. So then following those recommendations you just mentioned, what is recommended for patients with chemotherapy-induced peripheral neuropathy?

Dr. Jun Mao: So chemotherapy-induced peripheral neuropathy, also known as CIPN, is a very bothersome symptom resulting from certain types of chemotherapy that can be very functional limiting, and resulting in falls and that also can cut the dosage of chemotherapy. So this is a quite bothersome to patients and also can be really challenging in the practice of oncology. So based on the current evidence, we recommend either acupuncture or reflexology or acupressure may be offered to patients who experience CIPM. So, unfortunately, the evidence base here is weaker. So although it's evidence-based, benefits outweigh harms, but the quality of evidence is low. Therefore, the level recommendation is weak. So basically, there are a number of smaller trials that really provide some good signals that this type of therapies can be beneficial. But we really need more large and definitive trials to establish the strength of the evidence

Brittany Harvey: Understood. It's important to know in which patient populations we have more evidence and where we still need confirmatory results. So following those recommendations, what is recommended for patients who experience procedural or surgical pain?

Dr. Jun Mao: Many surgery procedures or surgery itself can cause acute short-term pain that if not adequately treated, can then become chronic. So in this setting, there is actually a pretty reasonably robust base for hypnosis. So the evidence base really is intermediate with moderate level recommendation. We consider that hypnosis may be offered to patients experiencing procedural pain in cancer treatment or diagnostic workups. However, for other type of therapies like acupuncture or acupressure or music therapy, although there are some smaller trials to show that it could be beneficial, the current evidence base is very low and the strength of recommendation is weak. So clearly, we need more high-quality trials to establish the evidence base for those therapies for surgery or procedure-related pain

Brittany Harvey: Understood, and we'll get into some of those outstanding questions or where there's insufficient evidence a little bit later in the episode. So then the last category of recommendations that the panel made: what is recommended for patients who have pain during palliative and hospice care?

Dr. Jun Mao: So for patients with advanced cancer near the end of life, there is some good evidence that massage may be offered for patients experiencing pain during palliative and hospice care. So we recommend massage should be used with an intermediate level of evidence and moderate level of recommendation. And I do think the caveat is we still don't know the long-term effects for massage. Therefore, many of the trials, the follow up are reasonably short. But the evidence showing that acupuncture in the population of palliative care hospice patients can produce immediate pain relief as well as to enhance coping. Therefore, we suggest massage may be offered to patients experiencing pain during hospice or palliative care settings.

Brittany Harvey: Understood. Well, thank you for reviewing all those recommendations, the level of evidence behind them and the strength of those recommendations. But you've also mentioned that in several areas, there's low evidence or insufficient evidence. So are there interventions that the panel reviewed but found insufficient or inconclusive evidence to make recommendations?

Dr. Jun Mao: Brittany, I feel like the field of integrative medicines research is still in its infancy or adolescence. So there's clearly a lot of gaps, particularly in the area of mindfulness-based interventions. There are studies showing outside oncology settings, it can be very helpful for managing pain and pain coping, but that literature in oncology is very, very limited to make any reasonable recommendation. So I think research is needed.

Another area is in the area of herbal medicine or supplements. A lot of cancer patients have a lot of interest in using supplements or herbs to manage symptoms, improve their sense of well-being. But the trials unfortunately in this setting are just too sparse and the quality is too poor to make any recommendation. Last but not least, is for children that experience pain. This guideline was sought out to develop recommendations for both adults and children. Unfortunately, the trials in the pediatric populations are just too few and some of the quality are just too poor. Therefore, there's inconclusive evidence in that population to recommend any specific therapy to be used to manage pain.

So I do think these represent really important gaps in research that we really need to be developing and designing and conducting rigorous clinical trials to build an evidence base so we can bring integrative medicine into conventional oncology care to help patients with a variety of truths.

Brittany Harvey: Yes, well, we certainly appreciate the panel reviewing this mountain of evidence across several different integrative oncology approaches, even if we ended up not making recommendations for certain interventions because of inconclusive or insufficient evidence because it still demonstrates the need for high-quality trials in those areas. In your view, Dr. Mao, what is the importance of this guideline? And how will it change clinical practice?

Dr. Jun Mao: Brittany, I think this guideline is both important and timely. With the opiate epidemic experienced in the United States, managing pain for cancer patients and survivors is incredibly challenging. This is the first SIO and ASCO joint guideline for integrative medicine for pain. And for the first time, we have solid recommendations for specific integrative medicine modalities to care for patients and survivors with pain. I do think the implementation process will take time. First of all, we need to find ways to educate oncology providers as well as patients about the evidence base of this treatment so they can talk to their patients about this type of therapies.

Second of all, some of the therapies are not uniformly covered by insurance. So we do need better insurance coverage for integrative therapies such as acupuncture, massage, or reflexology for managed pain for cancer patients. So people from across socioeconomic areas can access it.

I think last but not least, as we know, there are disparities in healthcare infrastructures. In large hospitals like Memorial Sloan Kettering Cancer Center, Dana-Farber, or MD Anderson Cancer Center, we do have acupuncture services developed to help cancer patients. But then in smaller community hospitals, especially in those who serve predominantly black and brown populations, those services may not be in existence. So we need to partner with our community partners to develop the necessary resources to overcome those structural barriers for these therapies to be incorporated as part of standard oncology care.

Brittany Harvey: Definitely. Those are key points on the implementation of this guideline and the availability and accessibility of integrative medicine modalities across different hospitals and patients. So then, this leads into my next question, how will these guideline recommendations impact patients?

Dr. Jun Mao: It is my hope this will really help improve patient care, and also patients here in such  conventional oncological treatments,  whether they're chemo therapies or hormonal treatments. I do think patients in general have a lot of preferences for using therapies that are a little bit more natural or therapies are in addition to drugs to manage their pain or symptoms. So these guidelines clearly provided recommendations based on prior research. And I do think as we engage patients in shared decision making, we need to really acknowledge patients’ beliefs, preferences, as well as availability of treatments in their care settings. So hopefully we can provide both evidence-based and patient-centered care to manage pain.

Brittany Harvey: It's great to have more options beyond conventional treatments to offer patients to help with pain management because it occurs across cancer patients. Finally, Dr. Mao, you've already talked about some interventions where we lacked data such as mindfulness-based interventions, herbal medicines and supplements, and interventions in the pediatric population. But what are the outstanding questions for the use of integrative approaches and managing pain in patients with cancer?

Dr. Jun Mao: Brittany, as a researcher, I'm always thinking about the future questions. I do think with clinical trials in the last 10 years, there's definitely larger and well done trials to demonstrate both efficacy and effectiveness of specific integrative medicine therapies for improving pain. We need to do more of that in the next 10, 20 years. In addition, I think two particular areas of research I hope to see more research as part of these guidelines being implemented, one is what I consider precision pain management. But just because acupuncture works for some patients, it doesn't work for everyone. We need to figure out what type of molecular biomarkers, so psychological attributes can help to predict who may respond to acupuncture or not so we can make sure the right person gets the right care for best pain management and at the least amount of cost to him or herself or to the society.

The second issue I really think we’ve got to do better is I feel like there's wide acknowledgement of health disparity in pain management, particularly in cancer patients. I'd love to see more research designed for and in populations of historically underserved populations, so we can really implement this approaches to narrow the health disparity issues in cancer care.

Brittany Harvey: Absolutely. Those are key points about providing equitable care for pain management in oncology. So I want to thank you for all of your work on these guidelines, Dr. Mao, and thank you for taking the time to speak with me today.

Dr. Jun Mao: Brittany, it’s such a pleasure. Thank you so much.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/survivorship-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available on iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

An interview with Dr. Beverly Moy from Massachusetts General Hospital in Boston, MA, lead author on "Chemotherapy and Targeted Therapy for HER2-Negative Metastatic Breast Cancer That is Either Endocrine-Pretreated or Hormone Receptor-Negative: ASCO Guideline Rapid Recommendation Update." Dr. Moy reviews data from the recently published DESTINY-Breast04 study, and the ASCO Expert Panel's updated recommendation on the use of trastuzumab deruxtecan. For more information, visit www.asco.org/breast-cancer-guidelines.

TRANSCRIPT

Brittany Harvey: Hello, and welcome to the ASCO Guideline podcast series brought to you by the ASCO podcast network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts.

My name is Brittany Harvey, and today I’m interviewing Dr. Beverly Moy from Massachusetts General Hospital in Boston, Massachusetts, lead author on 'Chemotherapy and Targeted Therapy for HER2-Negative Metastatic Breast Cancer That is Either Endocrine-Pretreated or Hormone Receptor-Negative: ASCO Guideline Rapid Recommendation Update'. Thank you for being here, Dr. Moy.

Dr. Beverly Moy: It’s my pleasure. Thank you for having me.

Brittany Harvey: Great. First, I’d like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology.

Dr. Moy, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Beverly Moy: I do not have any relevant disclosures that are directly relevant to this guideline topic.

Brittany Harvey: Thank you. Then let’s talk about this rapid update. So first, what prompted a rapid update to this guideline on chemotherapy and targeted therapy for patients with HER2-negative metastatic breast cancer that is either endocrine-pretreated or hormone receptor-negative, which was last updated in 2021?

Dr. Beverly Moy: First, I would state that ASCO issues rapid guideline recommendation updates when really important advances in the treatment and management of cancer have been presented. This mechanism really allows clinicians to keep up with the rapid advances in cancer management. The fact that a rapid update had to be issued just one year after the full updated guideline that was published in 2021, as you just mentioned, is really a testament to the advances in cancer research and clinical trials that have been made recently.

But I will state that the reason why this rapid update was done was because the result of the DESTINY-Breast04 study were so strong and compelling and showed such a large degree of benefit to a large group of metastatic breast cancer patients that we felt as the guideline panel that this rapid update had to be out there. We really wanted to make sure that the oncology community was aware of these results. That’s based on the strength of the trial. The DESTINY-Breast04 trial was a very large randomized study that showed that trastuzumab deruxtecan significantly improved progression-free survival and overall survival compared to treatment of physician’s choice in patients with metastatic, “HER2-low” breast cancer.

Brittany Harvey: So then based off this new data from the DESTINY-Breast04 trial that you just mentioned, what is the updated recommendation from the guideline expert panel?

Dr. Beverly Moy: So the updated recommendation is that patients with HER2-low, or to be specific, HER2 IHC1+ or 2+ and ISH negative metastatic breast cancer who have received at least one prior chemotherapy for metastatic disease, if they’re hormone receptor-positive, are refractory to endocrine therapy, those patients should be offered treatment with trastuzumab deruxtecan.

Brittany Harvey: And then what should clinicians know as they implement this new recommendation for trastuzumab deruxtecan?

Dr. Beverly Moy: I think that there are a few things that clinicians really need to be aware of. One is that it significantly improved progression-free survival and overall survival, and that’s pretty important. The paper was published in the New England Journal of Medicine, and folks can refer to that study specifically. But to be specific, it improved progression-free survival at a median follow-up of about 18 months from 9.9 months with trastuzumab deruxtecan compared to 5.1 months with treatment of physician choice in the entire study population. Median overall survival was 23.4 months with trastuzumab deruxtecan and 16.8 months with treatment of physician’s choice. So that’s really a marked improvement in both of those outcomes.

It is also important to note that trastuzumab deruxtecan has a very important side effect, and that’s the potential of developing drug-related interstitial lung disease or pneumonitis. And that could be very serious. This side effect was confirmed in about 12% of the patients who received trastuzumab deruxtecan, and about 1.3% of patients actually had severe symptoms requiring oxygen, and three patients in the study, so less than 1% actually died of this side effect. So that’s something that needs to be monitored for very carefully, and clinicians need to be very cognizant of this potential side effect when using this drug.

Brittany Harvey: Thank you for reviewing both the impact on survival and then the adverse event of interstitial lung disease. So how does this guideline update impact patients with breast cancer?

Dr. Beverly Moy: So metastatic breast cancer is incredibly common. And this HER2-low, and I say, “HER2-low” because this is a definition that has never been made before. The patients with HER2 IHC1+ or 2+ and ISH negative disease, that's a very large group of patients. That's a lot of patients. So it's really important that this guideline is going to impact a very large group of patients. Again, it's those who've had at least one prior line of chemotherapy in the metastatic setting. And if they had hormone receptor-positive disease, it has to be refractory to endocrine therapy. But that's a lot of patients. And the results of this randomized study do show that trastuzumab deruxtecan is superior to other treatment of physician’s choices that were available before this study came out in terms of its efficacy. So this guideline is very significant for clinicians and metastatic breast cancer patients across the world.

Brittany Harvey: Definitely. It's great to have a new option and one that has such a great clinical impact for patients.

So then finally, Dr. Moy, what are the outstanding questions regarding chemotherapy and targeted therapy for HER2-negative metastatic breast cancer?

Dr. Beverly Moy: I think like any good study, this raises a lot of other important questions. Again, this HER2-low definition that I described is an interesting one. It’s a very large bucket of patients. One obvious question is, would this drug be as effective in patients who are truly HER2-negative, so HER2 IHC of 0? Kind of, overnight, the results of this study has changed the paradigm for many oncologists because we used to just say HER2-positive or HER2-negative. And now we're looking back at patients' charts to see what their immunohistochemistry results were. Does it really matter if it's IHC 0 or 1+ or 2+? So that would be very interesting.

Another outstanding question is: what about the use of trastuzumab deruxtecan earlier in the treatment? I said that it should be offered for patients who’ve received at least one prior line of chemotherapy? What about first line chemotherapy in the metastatic setting? And there are multiple studies studying this drug in actually early stage breast cancer as well. So lots of unanswered questions about this compound that's pretty remarkable.

Brittany Harvey: Great. Well, I want to thank you so much for your time today, Dr. Moy, for discussing the results of the DESTINY-Breast04 trial with me, and for your work to rapidly update this guideline.

Thank you so much.

Dr. Beverly Moy: Thank you, Brittany. It was a pleasure.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

An interview with Dr. Ishmael Jaiyesimi from Beaumont Health Royal Oak and Oakland University William Beaumont School of Medicine in Royal Oak, MI, and Dr. Andrew Robinson from Kingston General Hospital, Queen's University in Ontario, Canada, authors on "Therapy for Stage IV Non-Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline." Dr. Jaiyesimi and Dr. Robinson review the latest recommendation updates for first-, second-, and third-line therapy in patients with stage IV NSCLC without driver alterations. Read the full guideline at www.asco.org/thoracic-cancer-guidelines.

TRANSCRIPT

An interview with Dr. Ishmael Jaiyesimi from Beaumont Health Royal Oak and Oakland University William Beaumont School of Medicine in Royal Oak, MI, and Dr. Andrew Robinson from Kingston General Hospital, Queen's University in Ontario, Canada, authors on "Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline." Dr. Jaiyesimi and Dr. Robinson review the latest recommendation updates for therapeutic options for patients with stage IV NSCLC with ALK rearrangement or RET rearrangement. They also discuss new agents on the horizon. Read the full guideline at www.asco.org/thoracic-cancer-guidelines.

TRANSCRIPT

Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs, covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows including this one at asco.org/podcasts.

My name is Brittany Harvey and today I'm interviewing Dr. Ishmael Jaiyesimi from Beaumont Health Royal Oak and Oakland University William Beaumont School of Medicine in Royal Oak, Michigan, and Dr. Andrew Robinson from Kingston General Hospital at Queen's University in Ontario, Canada, authors on 'Therapy for Stage IV Non-small Cell Lung Cancer with Driver Alterations: ASCO Guideline Update'.

Thank you for being here, Dr. Jaiyesimi and Dr. Robinson.

Dr. Ishmael Jaiyesimi: Thank you.

Dr. Andrew Robinson: It’s a pleasure to be here.

Brittany Harvey: Great! First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline.

The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology.

Dr. Jaiyesimi, do you have any relevant disclosures that are directly related to this guideline?

Dr. Ishmael Jaiyesimi: None.

Brittany Harvey: Thank you. And, Dr. Robinson, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Andrew Robinson: Yes, I have received funding less than $5,000 from AstraZeneca, Merck, and BMS over the past two years.

Brittany Harvey: I appreciate those disclosures. So, then Dr. Jaiyesimi, let's talk about the purpose of this guideline. So, what is the purpose of this guideline update, and what clinical scenarios does this guideline address?

Dr. Ishmael Jaiyesimi: The purpose of therapy for stage IV non-small cell lung cancer with driver alterations, is to rapidly update the ASCO and Ontario Health guideline on the systemic treatment of patients with stage IV non-small cell lung cancer, last published in February of 2021.

The update is a result of potentially practice-changing evidence published since the last publication in February 2021. The update is based on two clinical trials from 2020 to 2021.

The clinical scenario this guideline covers are stage IV non-small cell lung cancer with driver alteration with an ALK gene rearrangement and RET gene rearrangements.

Brittany Harvey: Great. So, then let's review those two clinical scenarios that you just mentioned. So, there are a few new recommendations regarding ALK rearrangement. So, what are the recommended first-line options for patients with stage 4 non-small cell lung cancer in an ALK rearrangement?

Dr. Ishmael Jaiyesimi: In the previous guideline alectinib or brigatinib were recommended as first-line therapy with a strong recommendation and level of evidence in patients with ALK gene rearrangement, and a performance status of zero to two.

In the current update, lorlatinib was cited as the first-line ALK inhibitor that may be offered as an alternative first-line therapy. If alectinib, brigatinib, or lorlatinib are not available, ceritinib or crizotinib should be offered.

This is based on the CROWN study that showed alectinib was superior to crizotinib in the first-line setting. Unfortunately, we don't have head-to-head comparative data with alectinib or brigatinib, so we cannot conclude that any one treatment is more effective than the other, and decisions should be made on experience, toxicity, and on.

Brittany Harvey: Okay, thank you for describing how a clinician should select between those treatments as well. So, then the second clinical scenario that Dr. Jaiyesimi just mentioned, Dr. Robinson, what is recommended for both first-line and second-line treatment for patients with stage IV non-small cell lung cancer and a RET rearrangement.

Dr. Andrew Robinson: Thank you. So, for patients with a RET rearrangement and a good performance status of zero to two and previously untreated non-small cell lung cancer, clinicians may offer selpercatinib or pralsetinib as first-line therapy.

Selpercatinib was recommended in the 2020 guidelines and pralsetinib has been added to that. As with other driver mutation recommendations for scenarios where randomized studies against standard non-driver mutation treatments have not been done or completed, these recommendations are with a lower level of evidence and somewhat weaker recommendations, an alternative approach of first-line standard non-driver mutation treatment may also be offered.

As a guideline group, we listed this approach of non-driver treatment behind the targeted therapies, because there's a belief that the targeted approach may be superior upfront. But we should also continue to, of course, encourage participation in ongoing trials comparing selpercatinib or pralsetinib to standard first-line non-driver mutation treatment to determine whether our assumptions are correct.

For patients with a RET rearrangement who've had previous RET targeted therapy, clinicians may offer treatment as per the non-driver mutation guidelines. And for patients with a RET rearrangement who have had previous chemotherapy, chemoimmunotherapy, clinicians may offer selpercatinib or pralsetinib for them.

Brittany Harvey: Okay. And then you've just mentioned some ongoing trials as well. So, that leads to my next question of what ongoing trials and new agents is the panel monitoring for the next guideline iteration?

Dr. Andrew Robinson: It's really an exciting time with new agents on trials and I think we can divide it into more driver mutations, more lines of therapy, and more certainty with what we're doing.

In terms of driver mutations, there are several phase II and III trials with agents such as sotorasib and adagrasib in KRAS-G12C mutated non-small cell lung cancer, trastuzumab deruxtecan in the DESTINY trials in HER-2 mutated lung cancer, mobicertinib and amivantamab in EGFR, exon 20 insertion lung cancer or HER-2 exon 20 insertion lung cancer, etc.

So, looking at more driver mutations is all of those agents plus a number of others that will be coming out over the next couple of years at ASCO. We're also interested in more lines of therapy.

So, for patients who progress after standard first-line, say osimertinib with EGFR or after progression on ALK therapies such as lorlatinib. So, we're looking forward to studies such as the CHRYSALIS studies of amivantamab and lazertinib in EGFR mutation-positive patients who have progressed after osimertinib, and other studies that are looking at the increasing treatment options for second-line treatment and third-line treatment.

And then we're looking at interest to phase three studies that are comparing targeted agents to docetaxel in the second-line setting such as the sotorasib studies in KRAS-G12C patients and capmatinib and MET exon 14 patients, particularly as many of these patients may do well with non-driver mutated guided first-line treatment.

There are phase three trials comparing RET inhibitors to standard first-line chemoimmunotherapy which will also be keenly awaited to see if our, and when I say our, I mean, the ASCO guideline panel and also the thoracic oncology community writ large, our assumption that targeted therapy will be superior to first-line therapy is actually borne out with clinical trial evidence.

So, there's plenty of evidence that we're excited to keep our eye on and update as soon as possible, which is more driver mutations, more lines of therapy for patients who have established driver mutations, and more certainty, hopefully, regarding the timing of these various interventions.

Brittany Harvey: Definitely, there's a lot going on in this space. So, we'll look forward to the results from these ongoing trials and the panel's review of that evidence, and eventually updated recommendations. So, then Dr. Jaiyesimi, in your view, why is this guideline update important and how will it impact practice?

Dr. Ishmael Jaiyesimi: This guideline is important because it emphasizes rapid development in the research and treatment in advanced non-small cell lung cancer and that non-small cell lung cancer are heterogeneous.

Clinicians need to identify biomarkers of the molecular pathways, including targetable driver mutations, example: epidermal growth factor receptors, the BRAF, the MET, the KRAS, and etcetera, and fusion rearrangement, example: anaplastic lymphoma kinase, c-ROS oncogene 1, RET, and on that drive malignancy in patients with non-small cell lung cancer, especially in those patients with adenocarcinoma histology and a little or never smoking history regardless of histology. Because of the availability of effective targeted agent for many of these cancers, at minimum, determination of epidermal growth factor receptor mutation status and anaplastic lymphoma kinase rearrangement status before initiating therapy because rapid and sensitive tests are available. An initiation of immunotherapy could increase the toxicity of tyrosine kinase inhibitors later in the patient’s course. All this, in my opinion, will impact clinical practice. Furthermore, an opportunity for patients with driver mutation to enrolled in ongoing clinical trials targeting the driver mutations.

Brittany Harvey: Yes. You've just mentioned that this is not a one size fits all approach for patients. And so, in your view, Dr. Jaiyesimi, how do these guideline recommendations affect patients living with stage IV non-small cell lung cancer with driver alterations?

Dr. Ishmael Jaeysimi: I believe along with my associates the improvement in the treatment of stage IV non-small cell lung cancer brings hope to the patient with driver alteration for a possibility to use targeted therapy and no chemotherapy or immunotherapy upfront to some patients and this may enhance their lives, increase longevity with some tolerable side effects, and better quality of life, and a truly wide range of opportunities for patients to participate in clinical trials.

Brittany Harvey: Great! Yes, it seems like the data has come fast, and a lot of new results of recent trials have driven these updated recommendations and we're also looking forward to many of the results from upcoming clinical trials that you both mentioned.

So, I want to thank you so much for your work on these guideline updates, and thank you for taking the time to speak with me today, Dr. Jaiyesimi and Dr. Robinson.

Dr. Ishmael Jaiyesimi: Thank you, Brittany.

Dr. Andrew Robsinson: It was a pleasure to be here and I hope that this was educational.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline go to www.asco.org/thoracic-cancer-guidelines. There's a companion guideline update on therapy for stage IV non-small cell lung cancer without driver alterations available there and on the JCO.

You can also find many of our guidelines and interactive resources in the free ASCO guidelines app available on iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO the mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

An interview with Dr. Lynn Henry from the University of Michigan in Ann Arbor, MI, lead author on "Biomarkers for Systemic Therapy in Metastatic Breast Cancer: ASCO Guideline Update." Dr. Henry reviews new biomarkers for the purposes of making treatment decisions for triple-negative breast cancer, and hormone receptor-positive, HER2-negative breast cancer, as well as tumor agnostic tumor biomarkers. Specific biomarkers addressed in this conversation include PIK3CA, ESR1, BRCA 1/2, PALB2, HRD, PD-L1, dMMR/MSI-H, TMB, NTRK, ctDNA, and CTCs. Read the full guideline at www.asco.org/breast-cancer-guidelines.

TRANSCRIPT

Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs, covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows including this one at asco.org/podcasts.

My name is Brittany Harvey and today I'm interviewing Dr. Lynn Henry from the University of Michigan in Ann Arbor, Michigan, lead author on 'Biomarkers for Systemic Therapy in Metastatic Breast Cancer: ASCO Guideline Update'.

Thank you for being here, Dr. Henry.

Dr. Lynn Henry: Thank you very much for inviting me to participate.

Brittany Harvey: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline.

The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology.

Dr. Henry, do you have any relevant disclosures that are related to this guideline topic?

Dr. Lynn Henry: No, I do not.

Brittany Harvey: Great! Thank you. Then let's talk about the scope of this guideline. So, what prompted this update to the guideline on the use of biomarkers to guide decisions on systemic therapy for patients with metastatic breast cancer, which was last updated in 2015? And what is the scope of this guideline update?

Dr. Lynn Henry: Yes, so a lot has happened in the past six or seven years that influence how we treat metastatic breast cancer. And there are many new drugs that have been approved by the FDA during that time.

When we reviewed the prior guideline and the new treatment landscape, we realized that while much of what was included in the old guideline was still relevant, there were quite a number of new biomarkers related to new drugs that needed to be included.

The newly recommended biomarkers are primarily applicable to making decisions about treatment of estrogen receptor, progesterone receptor, and HER2-negative breast cancer, also called triple-negative breast cancer, as well as for treatment of hormone receptor-positive HER2-negative breast cancer. And finally, there are now some tumor biomarkers that can be tested for that are tumor agnostic, and these were included as well.

Brittany Harvey: Great! So, then let's discuss the updated guideline recommendations based off these new biomarkers for our listeners. The guideline reviews testing for several different biomarkers. So, I would like to review each of the biomarkers that the panel assessed. Let's start with what is the role of PIK3CA mutation testing?

Dr. Lynn Henry: Yeah! So, PIK3CA activating mutations are commonly found in tumors that are hormone receptor-positive and HER2-negative. Based on the results of the SOLAR-1 trial, patients whose tumors have an activating PIK3CA mutation had improved progression-free survival when treated with the PI3 kinase inhibitor alpelisib plus fulvestrant compared to fulvestrant alone.

This improvement was not seen in patients whose cancers didn't have a mutation. So, therefore, this provided the evidence for the clinical utility of evaluating tumors for the somatic PIK3CA mutations.

Testing of either a tumor specimen or plasma to look for PIK3CA mutations can be performed. However, it's important that if the plasma is tested, and no PIK3CA mutations are identified in the circulating tumor DNA, then our tumor specimen should really be tested if possible, because of the possibility of a false negative finding in the plasma.

Also, since these mutations can be acquired over time, a more recent specimen should be tested if possible, as opposed to testing the primary tumor.

Finally, in the SOLAR-1 trial, a patient's tumor had to have one of the 11 pre-specified PIK3CA mutations in exon 7, 9, or 20. And therefore, when mutations are identified using next-generation sequencing, it is important to confirm that the identified mutation is one of those 11 activating mutations and not a different one that may not convey benefit from treatment with a PI3 kinase inhibitor.

Brittany Harvey: Great! I appreciate you're reviewing that recommendation, as well as the clinical utility of it and the evidence behind it. So, then following those recommendations, what is the role of testing for ESR1 mutations?

Dr. Lynn Henry: At this time, there are insufficient data to support routine testing of metastatic hormone receptor-positive HER2-negative tumors for ESR1 mutations. However, the panel did note that there's a retrospective analysis of two different phases three trials that demonstrated that fulvestrant improved progression-free survival compared to the aromatase inhibitor exemestane in patients who had previously progressed on a non-steroidal AI and whose tumors had an ESR1 mutation.

Importantly, there are ongoing clinical trials addressing this issue, including the PADA-1 trial, which is evaluating the effect of the switch of fulvestrant from aromatase inhibitor therapy, versus remaining on that therapy when ESR1 mutations are detected in the blood. However, although preliminary findings were presented at a recent large breast cancer meeting, and were suggestive of a possible progression-free survival benefit from switching therapy, data have not yet been published, and therefore they were not included in this guideline.

Brittany Harvey: Great! So, we'll look forward to those updated data to potentially review that recommendation in the future. So, following those recommendations, what is the role of testing for germline BRCA 1 or 2 and PALB2 pathogenic mutations?

Dr. Lynn Henry: So, the answer for germline BRCA1 and BRCA2 mutations is relatively straightforward. Patients with metastatic HER2-negative breast cancer can be either hormone receptor-positive or negative, and who are candidates for treatment with a PARP inhibitor should undergo testing for germline BRCA1 and BRCA2 pathogenic or likely pathogenic mutations to determine whether they should receive treatment with a PARP inhibitor.

This recommendation is based on the results of two large randomized clinical trials comparing PARP inhibitor therapy to physician's choice chemotherapy, although notably, the chemotherapy options did not include taxanes, anthracyclines, or platinums.

In contrast, there remains insufficient evidence to support a recommendation either for or against testing for germline PALB2 pathogenic variant for the purpose of determining eligibility for treatment with a PARP inhibitor.

The panel did note, however, that there are small single-arm studies that show that there is high response rate to PARP inhibitors in patients with metastatic breast cancer and coding DNA repair defects, such as either germline PALB2 pathogenic variants or somatic BRCA1 or 2 mutations. It was also noted that it is likely that patients who harbored mutations in these genes will actually be identified through routine testing with panel testing for germline variants.

Brittany Harvey: Okay, understood. So, then following those recommendations, what is the role of testing tumors for homologous recombination deficiency?

Dr. Lynn Henry: So, although there are emerging data from other solid tumors to support the use of homologous recombination deficiency, or HRD testing to guide therapy, current data do not support the assessment of HRD in the management of metastatic breast cancer. Therefore, we did not recommend routine testing of tumors for HRD at this time.

Brittany Harvey: It's important to note where we both have evidence and where we don't have evidence. So, then what is the role of testing for expression of PD-L1 in metastatic breast cancer?

Dr. Lynn Henry: So, the panel recommends that patients who are candidates for treatment with immunotherapy, with either a PD1 or PD-L1 inhibitor, should undergo testing for expression of PD-L1 in the tumor and immune cells with an FDA-approved test.

At present in the United States, pembrolizumab is the only approved immunotherapy for the treatment of metastatic breast cancer, and it is given in combination with chemotherapy.

The FDA-approved test for this drug is the 22C3 assay which evaluates PD-L1 staining in the tumor and surrounding stroma to calculate a combined positive score or CPS, with positive considered to be a score of 10 or greater.

Of note, in other countries, there are different anti PD1 and PD-L1 antibodies that are approved for treatment, and each has been approved with its own companion diagnostic. So, it is important to make sure that you're using the right biomarker test, depending on which drug you are planning to use.

Brittany Harvey: Great! I appreciate you reviewing the test in addition to the role of the biomarker. So, then, following those recommendations, what is the role of testing for deficient mismatch repair microsatellite instability-high?

Dr. Lynn Henry: Similar to PD-L1 testing, it is recommended that patients with metastatic breast cancer who are candidates for a treatment regimen that includes an immune checkpoint inhibitor should undergo testing for deficient mismatch repair or microsatellite instability-high to determine eligibility for treatment with one of the drugs that is currently FDA approved, either dostarlimab or pembrolizumab.

In contrast to the PD-L1 data, however, there are no randomized studies that have been conducted specifically in patients with breast cancer addressing this question. The testing recommendation was therefore included in these guidelines because of the tumor agnostic FDA approval of these drugs.

In terms of which biomarker methodology to use, it was noted that, while the original studies assessed the deficient mismatch repair and MSI high using immunochemistry, and PCR respectively. The FDA has subsequently approved the next-generation sequencing platform to use in selecting candidates for these treatments. And so, therefore, there are a number of different tests that can be used.

Brittany Harvey: Thank you for reviewing those recommendations as well. So, then following, what is the role of testing for tumor mutational burden?

Dr. Henry Lynn: So, tumor mutational burden describes the quantity of somatic mutations in the tumor. Similar to the biomarkers we were previously discussing, there are minimal data specifically in metastatic breast cancer to support the assessment of tumor mutational burden for making treatment decisions.

However, the testing recommendation was again included in the guidelines because of the tumor agnostic FDA approval of the drug pembrolizumab in the setting of high TMB. And also there is one single arm phase two trial that looked at this specifically.

Importantly, the panel noted that there are a variety of factors that influence assessment of TMB. These include sample type, pre-analytical factors so how the sample was handled, the size of the panel and mutations that are tested, depths of the sequencing, type of the mutations that are included on the panel, and cut point variables.

So, in particular, assessment of TMB in cell-free DNA assays such as circulating tumor DNA is an area of evolving evidence. There are therefore very important caveats to be aware of when selecting a TMB assay and assessing the results, many of which are outlined in the guideline manuscript itself, and different assays can yield different results for the same tissue specimen. It is therefore very important to use the approved companion assay and the approved cut point when making decisions regarding a specific treatment.

Brittany Harvey: Absolutely. I appreciate your reviewing those details. So, then what is the role of testing for neurotrophic tyrosine receptor kinase?

Dr. Lynn Henry: So, I'm going to abbreviate that to NTRK. So, NTRK fusions are rare in metastatic breast cancer. One study said 0.39% of all breast cancers have NTRK fusions.

So, as with the above biomarkers, the NTRK testing recommendation is based on the results of phase 1 and phase 2 studies that were identified by the panel evaluating the efficacy and safety of these inhibitors for the treatment of advanced solid tumors with NTRK gene fusions, noting that there are only minimal data available that are specific to metastatic breast cancer.

Brittany Harvey: Understood. Some of these are very rare in metastatic breast cancer. So, then, following that recommendation, what is the role of using circulating tumor DNA?

Dr. Lynn Henry: So, for circulating tumor DNA, although the ctDNA technology holds promise in metastatic disease, for its ability to potentially identify tumor-specific mutations that are shed into the blood and that may be targetable, to date, neither the measurement of changes in ctDNA as a marker of treatment responsiveness nor identification of specific mutations in the blood to direct therapy has actually been prospectively shown to improve patient outcomes compared to standard imaging-based detection of tumor progression.

Therefore, at present, the guideline does not recommend routine assessment of ctDNA for monitoring response to therapy among patients with metastatic breast cancer, although many studies are underway evaluating this question.

Brittany Harvey: Understood. Then the last biomarker that the panel assessed in this guideline update, what is the role of using circulating tumor cells?

Dr. Lynn Henry: Similar to circulating tumor DNA, there are insufficient data to recommend routine use of circulating tumor cells to monitor response to therapy among patients with metastatic breast cancer.

To date, studies that have examined the clinical utility of this marker to determine the optimal time for treatment change have not led to improvements in outcomes in metastatic breast cancer.

Brittany Harvey: Great! Well, thank you for reviewing all of these recommendations. The panel certainly took on a lot of biomarkers and performed a critical review of all the evidence to make recommendations in this setting. So, in your view, Dr. Henry, what is the importance of this guideline update and what should clinicians know as they implement these updated recommendations?

Dr. Lynn Henry: Yeah, that's an excellent question. So, this guideline addresses the key questions that we face, as we're making decisions about how best to treat patients with metastatic breast cancer.

Importantly, the guideline highlights the current state of the science, with a focus on the available published data from randomized clinical trials. It also discusses the limitations of our current knowledge, as well as key considerations for different biomarkers.

Of course, we recognize that there are new data emerging on a regular basis. And the panel therefore also highlighted where data are anticipated but not yet available, as well as key questions which we hope will be able to be addressed in the more distant future.

Brittany Harvey: And then finally, how will these guideline recommendations affect patients with metastatic breast cancer?

Dr. Lynn Henry: Yeah, so really, that is the bottom line, isn't it? So, ideally, this guideline will enable the dissemination of best practices in terms of biomarker selection and analysis to guide clinicians as they are making treatment decisions in conjunction with patients.

Treatment of metastatic breast cancer has become more complex, with regimen selection affected by both inherited germline genetics and somatic changes in the cancer that can evolve over time. The assessment of relevant biomarkers should allow patients to receive the optimal therapies that are most likely to be effective based on the individual characteristics of their cancers.

Brittany Harvey: Well, I want to thank you so much for reviewing this guideline with me today, and all of the recommendations and our gaps in evidence, for our listeners. Thank you for your work on this guideline update and thank you for your time today, Dr. Henry.

Dr. Lynn Henry: Thank you so much!

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/breast-cancer-guidelines.

You can also find many of our guidelines and interactive resources in the free ASCO guidelines app available on iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

An interview with Dr. Tian Zhang from UT Southwester Medical Center in Dallas, TX, author on "Management of Metastatic Clear Cell Renal Cell Carcinoma: ASCO Guideline." Dr. Zhang reviews the guideline recommendations for the treatment and management of patients with metastatic clear cell renal cell carcinoma and it's implications for clinicians and patients. Read the full guideline at www.asco.org/genitourinary-cancer-guidelines.

An interview with Dr. Pauline Funchain from Cleveland Clinic in Cleveland, OH, author on "Systemic Therapy for Melanoma: ASCO Guideline Rapid Recommendation Update." Dr. Funchain reviews recent evidence and updated recommendations from the ASCO Expert Panel for the use of tebentafusp in patients with metastatic uveal melanoma. For more information, visit www.asco.org/melanoma-guidelines.

TRANSCRIPT

Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one at asco.org/podcasts.

My name is Brittany Harvey and today I am interviewing Dr. Pauline Funchain from Cleveland Clinic in Cleveland, Ohio, author on Systemic Therapy for Melanoma: ASCO Guideline Rapid Recommendation Update. Thank you for being here, Dr. Funchain.

Dr. Pauline Funchain: It's great to be here with you, Brittany. Thank you!

Brittany Harvey: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline.

The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology.

Dr. Funchain, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Pauline Funchain: I do not have relevant disclosures that relate to this guideline topic.

Brittany Harvey: Great, thank you. Then getting into the rapid update, what prompted this rapid update to the Systemic Therapy for Melanoma: ASCO Guideline published in 2020?

Dr. Pauline: So, earlier this year, on January 25th, the FDA approved tebentafusp for metastatic uveal melanoma. So, this is the first FDA approval for metastatic uveal melanoma. We felt it was really important to put out a rapid update to let both clinicians know about the therapy and also so that more patients can get access to it as quickly as possible.

Brittany Harvey: Understood. So, then based on this new FDA approval, what are the updated recommendations for patients with uveal melanoma?

Dr. Pauline Funchain: So, any patients who have a previously untreated metastatic uveal melanoma, and also who are HLA-A*02:01 positive, this group of patients should be offered tebentafusp as systemic therapy.

This is the only systemic therapy that has been shown to prolong overall survival in patients with metastatic uveal melanoma. And if you look at the kind of benefit that was seen, patients who were on tebentafusp had a median overall survival of 21.7 months versus 16 months in comparison to investigator's choice. In this case, that was either single agent pembrolizumab, ipilimumab, or dacarbazine. So, it is a pretty significant overall survival benefit.

Brittany Harvey: Great! Thank you for reviewing those updated recommendations and the data behind them. So, what should clinicians know as they implement this updated recommendation?

Dr. Pauline Funchain: So, they should know that there was a great overall survival benefit seen, but it doesn't correlate with the objective response rate that was seen in the trial. So, for patients who were treated with tebentafusp, the objective response rate was 9%. And for those patients who were treated with the investigator's choice, again, that was single agent pembrolizumab, ipilimumab, or dacarbazine, the response rate was 5%.

So, that margin was not very different in terms of objective response rate when looking at RECIST-based criteria, so radiologic criteria for response, but the survival was clearly seen. And interestingly, even in those patients that had radiologic progression, there was an improved survival for those patients who were on tebentafusp versus investigator's choice.

So, there is some kind of survival benefit that may not correlate with what is seen on imaging. So, clinicians should know that they may not see a dramatic response in terms of tumor size on imaging, but patients may still benefit from the therapy.

Brittany Harvey: Understood. So, then you've just talked a little bit about responses in patients. So, how does this guideline update affect patients with melanoma?

Dr. Pauline Funchain: So, despite a difference in response rate, long story short, there is an overall survival difference. So, really, this is the first overall survival difference that we have seen in metastatic uveal melanoma.

It is really exciting. It is finally an approved drug for metastatic uveal melanoma, which did not have any approved or standard of care, systemic drugs. So, this is a really big win for a rare disease. I think, in terms of the general melanoma field and also the cancer field in general, this is really an exciting first-in-class drug on two different fronts. It is the first approved T-cell receptor therapy. It is also the first bispecific protein and it works differently than other immunotherapies we have seen. So, hopefully, this is something we see more of in other cancers.

Brittany Harvey: Definitely, it's good to see that these patients finally have an option and we'll look forward to research in other cancers as well. So, then finally, Dr. Funchain, what are the outstanding questions regarding systemic therapy for melanoma?

Dr. Pauline Funchain: Well, there are multiple questions that are outstanding. I think, for metastatic uveal melanoma, I think there are a lot of questions about the dissociation between the radiologic response and survival. I think there are questions about knowing when to stop tebentafusp if it's not working because we don't really have a good sense of what we should be using to know if this is not the right therapy for that patient.

I think we would love to know what the biomarkers of response are, and we may need different ways of looking for how to judge if a patient is benefiting from tebentafusp and other systemic therapies. And I think that there's still a big question in uveal melanoma about whether we start with systemic therapy or local therapy. I don't think that's been answered.

Now, in terms of the entire guideline, I think for melanoma in general, there are new data that are emerging and have been recently published and we will be looking forward to the next ASCO guideline in systemic therapy for melanoma because I think that there are a lot of emerging data that need to be addressed.

Brittany Harvey: Definitely. We'll look forward to that new research in uveal melanoma and to reviewing the updated data with the guideline panel for the next edition of the systemic therapy for melanoma guideline. So, I want to thank you so much for your work to rapidly updating this guideline, and thank you for your time today, Dr. Funchain.

Dr. Pauline Funchain: Thank you for having me. It is really meaningful to us to be able to offer education and get the word out about therapies that can help our patients.

Brittany Harvey: Agreed. And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast series. To read the full rapid recommendation update, go to www.asco.org/melanoma-guidelines.

You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available on iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.